Personal lubricants comprising lambda-carrageenan

ABSTRACT

The present invention includes pourable, non-toxic lubricating compositions containing carrageenan and more precisely λ carrageenan as an anti-viral agent, for protection from Human Papillomavirus (HPV), and methods of using the lubricating compositions as a non-oily, psuedoplastic lubrication product and administering the carrageenan for reducing the propagation of HPV during sexual activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/391,653, filed on Apr. 23, 2019, which was a continuation-in-part ofU.S. patent application Ser. No. 16/359,168, filed on Mar. 20, 2019,which claimed the benefit of U.S. Provisional Application No.62/645,347, filed on Mar. 20, 2018, the disclosures of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to processes for making personal lubricantcompositions useful for reducing or inhibiting the transmission of humanpapillomavirus among partners during sexual activity.

BACKGROUND OF THE INVENTION

According to the World Health Organization (WHO), human papillomavirus(HPV) is the most common sexually transmitted infection (STI) in theworld, with over 14 million people acquiring new infections annually. Inthe United States alone, more than 42% of the people between the ages of18 and 59 are infected with HPV, and 1 out of every 9 men are infectedwith oral HPV. Additionally, HPV is the root cause of essentially allcervical cancers, the second most common cancer in women worldwide byage-standardized incidence rate, leading to approximately 500,000 deathsper year. More than 85% of cervical cancer deaths are in developingcountries, where it accounts for 13% of all female cancers. WHO alsoestimates that HPV causes 90% of anal cancer. In a separate study on HPVand throat cancer, AECOM found that the presence of an HPV type in themouth increases the odds of developing head and neck cancer bytwenty-two times. HPV is also the underlying cause of all genital warts.

HPV is spread from skin-to-skin contact, most commonly transmittedduring sexual activity to the genitals, anus, and mouth. Consequently,condoms are only marginally effective in preventing transmission of HPV.While there are some treatment options for HPV, the reality is thatthere are more than 150 strains of HPV, approximately 30 of which havebeen shown to cause cancers and genital warts. Vaccines have beendeveloped and can be useful—however, the best HPV vaccine available inthe United States today only provides antiviral activity against 9 ofthe more than 150 HPV strains and they are only efficacious for a smallsubset of people. In 2015, the CDC reported that HPV vaccines only havean uptake rate 40% among adolescents, and that they are generallyineffective for people over 26 years old, as well as African-Americanwomen of any age. Further, the CDC has also reported that vaccines arealso ineffective if the person has previously been exposed to HPV.Additionally, HPV vaccines are typically expensive, require multipletreatments or injections, and are largely unavailable to people indeveloping countries. As a result, a large proportion of people areunvaccinated and rely on condoms as their only protection against HPV.

There have been some promising studies about the use of carrageenanformulations, particularly formulations containing λ-forms ofcarrageenan, to reduce or inhibit the transmission of viruses in vitro(see Buck, C. B., et al., (2006) PLoS Pathogens 2 (7):671-680) and invivo in mice (see Roberts, J. N., et al., (2007) Nature Medicine 13(7):857-861, and Maguire, R. A., et al., (1998) Sexually TransmittedDiseases 25 (9):494-500). Several other patents and patent publicationssimilarly discuss the use of carrageenan within medicaments as anantimicrobial or antiviral compound (see U.S. Pat. Nos. 5,208,031 and8,367,098, and U.S. Pat. Pubs. 2005/0171053, 2005/0239742, 2005/0261240,2006/0127340, 2008/0227749, 2009/0088405, and 2011/0229446, thedisclosures of which are incorporated by reference in their entireties).

More recently, in vivo studies in humans have shown that λ-carrageenanformulations can be utilized to inhibit the transmission of HPV duringsexual activity (see Magnan, S., et al., (2019) Clin. Microbiol. Infect.25 (2):210-216, the disclosure of which is incorporated by reference inits entirety). Yet, there are very few commercially-available personallubricants that contain carrageenan because the carrageenans are verydifficult to process into a form that is suitable for use during sexualactivity. Carrageenans are large, highly flexible polysaccharides thatare almost exclusively obtained as complex mixtures of at least two, andtypically three, different forms: κ-carrageenan, ι-carrageenan, andλ-carrageenan, which differ in their degree of sulfation. κ- and ι-formsof carrageenan, which contain the fewest number of ester sulfate groupsper molecule, predominate most carrageenan mixtures and are typicallyused in the food or cosmetic industries as gelling or thickening agents.On the other hand, λ-carrageenan has the most ester sulfate groups perpolysaccharide, and is unable to form a gel at all. Increased estersulfate levels generally result in a lower solubility temperature inwater, and go hand in hand with decreased gel strength or inhibition ofgel formation, in the case of λ-carrageenan. When present, allcombinations of κ-, ι-, and λ-forms of carrageenan, as a function oftotal concentration of carrageenan in a composition, have an exponentialeffect on the composition's viscosity. This can cause a loss ofrheological, tactile, and performance benefits when the composition isused as a sexual lubricant. In particular, carrageenan-basedformulations are prone to drying quickly after being applied, resultingin sticky, non-lubricous residues that defeat the purpose of using apersonal lubricant in the first place. Additionally, the viscosity of aparticular carrageenan-containing composition is highly sensitive to theexact proportions of the κ-, ι-, and λ-forms within the composition.Thus, a composition that contains 50% λ-carrageenan and 50%κ-carrageenan will have a different viscosity than a composition thatcontains 70% λ-carrageenan and 30% κ-carrageenan, even where the totalconcentration of carrageenan in both compositions is identical. Thiseffect is exacerbated in compositions that comprise all three forms ofcarrageenan. Consequently, the viscosity of carrageenan-containingcompositions is generally not predictable from one composition to thenext when the proportions of the κ-, ι-, and λ-forms are different, evenwhen the total carrageenan concentration is the same.

Further, the processing steps themselves that are used to makecarrageenan-containing compositions can have an effect on the viscosityand performance as a sexual lubricant. For instance, the temperature atwhich components are mixed has a dramatic effect on the viscosity of acarrageenan-containing product, particularly as a function of the ratioof each form of carrageenan within the mixture. When unprocessedcarrageenan mixtures are placed in an aqueous-based solvent and heated,individual polysaccharides within the mixture begin to hydrate andintermolecularly interact with other polysaccharides, increasing theviscosity of the composition. As the temperature is increased further,intermolecular interactions are disrupted and the carrageenanshomogenize and are contained within an aqueous solution phase,decreasing the overall viscosity to near starting levels. However, theproportions of each form of carrageenan that are contained within thecomposition can affect what happens upon cooling. When the predominantform is κ- or ι-carrageenan, the cooled composition will form a gel,whereas when the predominant form is λ-carrageenan, the cooledcomposition will not form a gel. Nonetheless, the relative proportionsof κ- and ι-carrageenan within the composition nonetheless affect theviscosity in λ-carrageenan containing compositions that do not gel.

On the other hand, excessively heating carrageenan-containingcompositions can have the effect of breaking intramolecular bonds withinneighboring sugar units, effectively causing significant changes to thecarrageenan molecules and reducing their average molecular weight. Thiscan cause the viscosity of the resulting composition to decrease evenfurther, but comes with a trade-off of causing the composition to dryout even more quickly once it is applied. Similarly, mixingcarrageenan-containing mixtures for an extended period of time at highspeed or under high-shear conditions can also disrupt intra- andintermolecular relationships of the carrageenan molecules within thecomposition.

Consequently, there remains a need for formulation that containsλ-carrageenan and also performs satisfactorily as a sexual lubricantthat allows both men and women to protect themselves from HPVtransmission in a pleasant and unobtrusive fashion. The lubricantformulation must balance efficacy against HPV while retaining theviscosity, tactility, and performance enhancements gained by usingpersonal lubricants during sexual activity. There also remains a needfor a product that can be used in in conjunction with condoms or othersexual accessory devices that reduce the risk of transmitting HPV, HIV,and herpes during sexual activity, particularly in encounters involvingtwo or more men.

SUMMARY OF THE INVENTION

The present invention provides processes for making low-viscosity,antiviral lubricous compositions that include λ-carrageenan and areuseful for reducing, inhibiting, or ameliorating the transmission,persistence, or symptoms caused by HPV. The antiviral lubricouscompositions made according to the disclosed processes can be applied toany epithelial or skin tissue where HPV can reside or be spread,including the tissue within or on the cervix, vulva, vagina, clitoris,penis, anus, mouth, or throat. In some embodiments, the antivirallubricous compositions of the present invention are effective inreducing the transmission of HPV in humans, relative to placebocompositions that do not contain lambda-carrageenan. In furtherembodiments, the antiviral lubricous compositions provide protectionagainst the transmission of HPV, including transmission that occursduring male-female sexual encounters, male-male sexual encounters, andfemale-female sexual encounters. In some embodiments, the antivirallubricous compositions provide protection against the transmission ofHPV strains known to cause cancer, particularly cervical cancer. Infurther embodiments, the antiviral lubricous compositions provideprotection against the transmission of HPV among high-risk sexualpartners, including those who are already infected with at least onestrain of HPV.

In another embodiment, antiviral lubricous compositions made byprocesses of the present invention can be used in conjunction withsexual activity. In some further embodiments, the antiviral lubricouscompositions can be applied up to eight hours prior to sexual activity.In other further embodiments, the antiviral lubricous compositions canbe applied up to eight hours after sexual activity. In even furtherembodiments, sexual activity includes contact with the skin orepithelial tissue within or on the cervix, vulva, vagina, clitoris,penis, anus, mouth, or throat of one, two, or more sexual partners.

In another embodiment, the antiviral lubricous compositions arenon-Newtonian, pseudoplastic fluids that undergo thixotropic shearthinning that reduces the composition's viscosity even further inresponse to mechanical strain. As a non-limiting example, suchmechanical strain can occur when one, two, or more people engage insexual activity, including sexual activity between male and femalesexual partners, two or more male sexual partners, two or more femalesexual partners, and combinations thereof.

In another embodiment, the antiviral lubricous compositions possess arheological profile in which the lubricity of a dried antivirallubricous composition on the skin can be retained upon adding water orother bodily fluids to the dried antiviral lubricous composition.Non-limiting examples of bodily fluids include saliva and vaginalsecretions or discharge. In further embodiments, upon adding water orbodily fluids to the dried antiviral lubricous composition, theantiviral lubricous composition retains its activity against HPV.

In another embodiment, antiviral lubricous compositions made byprocesses of the present invention can be utilized independently ofengaging in sexual activity. In some embodiments, the antivirallubricous compositions can be utilized as a vaginal moisturizer. Inother embodiments, the antiviral lubricous compositions can be utilizedas a vaginal deodorizer. In further embodiments, the antiviral lubricouscompositions can be utilized as a vaginal odor eliminator.

In some embodiments, the antiviral lubricous compositions of the presentinvention can be prepared substantially free of components typicallyutilized in commercially-available personal lubricants, including butnot limited to: oils, particularly silicone oils; cellulose; andpolyquaterniums. In other embodiments, the antiviral lubricouscompositions can be prepared to be substantially free of spermicides,such as nonoxynol-9, that are also often present commercially-availablepersonal lubricants.

In another embodiment, processes to form antiviral lubricouscompositions of the present invention can comprise the steps of: (a)providing a carrageenan powder comprising carrageenan, the carrageenancomprising at least about 90% by weight λ-carrageenan and up to about10% by weight ι-carrageenan; (b) mixing the carrageenan powder with apolyol to form a wet carrageenan mixture, wherein the weight ratio ofthe polyol to the carrageenan is about 1:1 to about 10:1; (c) combining,while mixing, the wet carrageenan mixture with an aqueous solution toform a turbid carrageenan suspension, wherein the volume ratio of theaqueous solution to the wet carrageenan mixture is about 45:1 to about8:1; (d) heating the turbid carrageenan suspension up to a temperatureof at least 60° C. and mixing for a time sufficient to transform theturbid carrageenan suspension into a clarified homogeneous solution,thereby forming the antiviral lubricous composition; wherein (i) theantiviral lubricous composition comprises about 0.5% to about 2.3% byweight carrageenan, and up to about 10% by weight polyol; (ii) theantiviral lubricous composition has a viscosity of less than about 5,000cP; (iii) the antiviral lubricous composition is translucent; and (iv)the antiviral lubricous composition is effective in reducing,inhibiting, or ameliorating the transmission of human papillomavirus(HPV). In some embodiments, the polyol is propylene glycol.

In one embodiment, the step of mixing the wet carrageenan mixture withthe aqueous solution comprises dispersing the carrageenan contained inthe wet carrageenan mixture within the aqueous solution. In a furtherembodiment, the step of dispersing comprises sufficient shear mixing ofthe carrageenan powder with the polyol with a dispersing mixer for atime sufficient to homogenize the carrageenan into the aqueous solution,while also minimizing the breaking of intramolecular bonds between sugarresidues within each carrageenan polysaccharide.

In another embodiment, a step of mixing of other powdered, solid, orliquid adjuvants into the aqueous solution comprises agitating theadjuvants within the aqueous solution under sufficient shear mixing andfor a time sufficient to form a compositionally uniform solution.

In another embodiment, the carrageenan powder comprising λ-carrageenanis a dried extract from sea algae, particularly from the red algae,Chondrus crispus. In some embodiments, λ-carrageenan comprises at least80% by weight of the sea algae extract, which can be at least about 85%by weight, or at least about 90% by weight, of the sea algae extract,and particularly between about 80% by weight and about 90% by weight ofthe sea algae extract. In other embodiments, λ-carrageenan comprises upto about 100% by weight of the sea algae extract, which can be up toabout 99%, or 95%, or 90%, by weight of the sea algae extract.

In an embodiment of the invention, the carrageenan powder consists ofcarrageenan in powder form. In another embodiment, the carrageenanpowder consists essentially of carrageenan in powder form.

In a further embodiment, the carrageenan powder can comprise carrageenanin powder form and an additional powder component. Non-limiting examplesof an additional powder component includes a pH adjusting agent, adisinfectant, a preservative, a sweetener, and a salt.

In another embodiment, the carrageenan powder comprises at least about85% by weight λ-carrageenan, including at least about 90% by weight ofλ-carrageenan.

In another embodiment, the remaining carrageenans comprised within thecarrageenan powder consist of at least one of κ-carrageenan andι-carrageenan. In further embodiments, when present, κ-carrageenan andι-carrageenan together comprise up to about 10% by weight of thecarrageenan powder including up to about 8%, 6%, 4%, 2%, or up to about1% by weight of the carrageenan powder. In other embodiments, whenpresent, κ-carrageenan and ι-carrageenan together comprise at leastabout 1% by weight of the carrageenan powder, including at least about2%, 4%, or 6% by weight, up to at least about 8% by weight of thecarrageenan powder. In even further embodiments, κ-carrageenan andι-carrageenan together comprise about 1% to about 15% by weight of thecarrageenan powder. In still further embodiments, κ-carrageenan andι-carrageenan together comprise about 10% of the carrageenan powder. Ineven still further embodiments, ι-carrageenan comprises 10% of thecarrageenan powder. In other even still further embodiments, there issubstantially no κ-carrageenan in the carrageenan powder. In yet evenstill further embodiments, the carrageenan powder comprises 90%λ-carrageenan and 10% ι-carrageenan.

In another embodiment, antiviral lubricious composition comprises atleast about 0.001% by weight carrageenan, including at least about 0.01,0.1, 0.5, 0.75, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.5, or 3% byweight, up to at least about 5%. In other embodiments, the antivirallubricious composition comprises less than about 5% by weightcarrageenan, including less than about 3, 2.5, 2.4, 2.2, 2, 1.8, 1.6,1.4, 1.2, 1.0, 0.75, 0.5, 0.1, or 0.01% by weight, down to less thanabout 0.001% by weight. In further embodiments, the antiviral lubriciouscomposition comprises about 0.2% to about 2.3% by weight carrageenan. Ineven further embodiments, the antiviral lubricous composition comprises0.8% by weight to about 2% by weight carrageenan. In still furtherembodiments, the antiviral lubricous composition comprises about 1.5% toabout 1.7% by weight carrageenan.

In another embodiment, the addition of one or more polyols to thecarrageenan powder causes the carrageenan polysaccharides within thepowder to partially unwind, making additional polarizable contactsavailable to interact upon addition of the aqueous solution. In otherembodiments, the presence of polyols within the antiviral lubricouscomposition enhances the sensation, tactility, and/or lubricityexperienced by the wearer or his or her partners during sexual activity.In further embodiments, the at least one polyol can be selected from thegroup consisting of: glycerol; propylene glycol (1,2-propanediol);1,3-propanediol; polyethylene glycol; and polypropylene glycol;including combinations thereof. In even further embodiments, theantiviral lubricous composition comprises less than about 50% by weightpolyol, including less than about 25, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1,or 0.5% by weight, down to less than about 0.1% by weight of theantiviral lubricous composition. In other even further embodiments, theantiviral lubricous composition comprises at least about 0.1% by weightof polyol, including at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,15, or 25% by weight, including at least about 35% by weight of thepolyol. In still further embodiments, the antiviral lubricouscomposition comprises less than about 10% by weight polyol. In evenstill further embodiments, the antiviral lubricous composition comprisesabout 0.5% to about 5% by weight of the polyol. In other even stillfurther embodiments, the antiviral lubricous composition comprises about4% to about 5% by weight of the polyol. In some embodiments, the polyolis propylene glycol.

In another embodiment, the antiviral lubricous composition is a pourablecomposition that has a viscosity of less than about 10,000 cP, includingless than about 8,000, 6,000, 5,000, 4,000, 3,000, or 2,000 cP, down toless than about 1,000 cP. In other embodiments, the antiviral lubricouscomposition has a viscosity of at least about 500 cP, including at leastabout 1,000, 2,000, 3,000, 4,000, 5,000, or 6,000 cP, or at least 8,000cP. In further embodiments, the antiviral lubricous composition has aviscosity between about 500 cP and about 8,000 cP, more particularlybetween about 1,000 cP and about 4,000 cP, particularly between about2,000 cP and about 3,000 cP. In some embodiments, the antivirallubricous composition has a viscosity between about 1,500 cP and 2,500cP. In some embodiments, the antiviral lubricous composition has aviscosity of about 2,000 cP.

In another embodiment, the antiviral lubricous composition has aviscosity that enables it to be poured from an open container, yetremains on a surface upon application. Non-limiting examples of surfacesinclude skin or epithelial tissue such as the cervix, vulva, vagina,clitoris, penis, anus, mouth. Other non-limiting examples include sexualaccessories or devices such as sex toys, vibrators, rings, or beads, orinternal applicators such as swabs, elongate stick or rods, wearableinserts, injectors, syringes, cannulas, or pipettes.

In another embodiment, upon exerting one or more shearing forces to orusing the surface containing the applied antiviral lubricouscomposition, as is commonly applied during sexual activity, theviscosity of the antiviral lubricous composition decreases in anon-Newtonian manner. In further embodiments, the viscosity reduces toless than about 5,000 cP, including less than about 4,000, 3,000, 2,500,2,000, 1,500, 1,000, 800, 600, 500, 400, or 300 cP, down to less thanabout 200 cP. In other embodiments, the lubricity of the antivirallubricous composition is retained upon exerting the shearing forcescontinuously for at least 15 seconds, including at least 30 seconds, 1minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15minutes, 20 minutes, 30 minutes, or 45 minutes, up to at least one hour.

In another embodiment, increasing the total concentration of carrageenanwithin the antiviral lubricous composition has an exponential increaseon the composition's viscosity. In further embodiments, the relativeconcentration of the κ-, ι-, and λ-forms of carrageenan differentiallyaffect the rate of exponential growth of the viscosity of the antivirallubricous composition. In even further embodiments, the antivirallubricous composition comprises 90% λ-carrageenan and 10% of one or bothof κ-carrageenan or ι-carrageenan. In even still further embodiments,the antiviral lubricous composition comprises about 90% of λ-carrageenanand about 10% of ι-carrageenan.

In some embodiments, the weight ratio of the polyol to the carrageenanwithin the wet carrageenan mixture is at least 1:10, including at least1:5, 1:1, 2:1, 4:1, 6:1, 8:1, 10:1, 20:1, 30:1, or 40:1, up to at least50:1. In further embodiments, the weight ratio of the polyol to thecarrageenan is about 1:1 to about 10:1. In even further embodiments, thepolyol is 1,2-propanediol. In even further embodiments, the weight ratioof the aqueous solution mixed with the wet carrageenan mixture to formthe carrageenan suspension is about 3:1 to about 60:1. In still furtherembodiments, the weight ratio of the aqueous solution mixed with the wetcarrageenan mixture to form the carrageenan suspension is about 8:1 toabout 45:1.

In another embodiment, heating one or more of the wet carrageenanmixture, the carrageenan suspension, and/or the antiviral lubricouscomposition enables the solubilization and homogenization of thecarrageenans in water. In further embodiments, one or more of the wetcarrageenan mixture, the carrageenan suspension, and/or the antivirallubricous composition is heated to a temperature of at least about 60°C., including at least about 65° C., 70° C., at least about 70° C., 75°C., at least about 75° C., 80° C., at least about 80° C., 85° C., or 90°C., up to at least about 95° C. In even further embodiments, thecarrageenan suspension is heated. In still further embodiments, thecarrageenan suspension is heated to 70° C.

In another embodiment, the carrageenan suspension is turbid. Whensubstantially all of the carrageenans within the carrageenan suspensionare homogenized, the carrageenan suspension clarifies and the resultingantiviral lubricous composition is a translucent solution. In furtherembodiments, the antiviral lubricous composition becomes and remainstransparent upon homogenization. In even further embodiments, there aresubstantially zero particulates, aggregates, or agglomerates visiblewithin the antiviral lubricous composition.

In another embodiment, the turbidity of any of the mixtures,suspensions, or antiviral lubricous compositions disclosed herein can bedescribed quantitatively based on the method of determining theconcentration of suspended particles in the sample, including but notlimited to Formazin Nephelometric Units (FNU), Jackson Turbidity Units(JTU), and Nephelometric Turbidity Units (NTU). In further embodiments,the turbidity of any of the mixtures, suspensions, or antivirallubricous compositions described herein are characterized as a functionof NTU. In even further embodiments, the turbidity of the carrageenansuspension upon the addition of carrageenan to the aqueous solution isat least about 100 NTU, including at least about 200, 300, 400, 500,600, 700, 800, 900, 1000, 2000, or 3000 NTU, up to at least about 4000NTU. In other even further embodiments, the turbidity of the homogenizedantiviral lubricous composition is less than about 25 NTU, includingless than about 20, 15, 10, 8, 6, 5, 4, 3, or 2 NTU, down to less thanabout 1 NTU. In still further embodiments, the turbidity of thehomogenized antiviral lubricous composition is less than or equal toabout 5 NTU. In other still further embodiments, the turbidity of thehomogenized antiviral lubricous composition is approximately equal tothe turbidity of drinking water.

In another embodiment, an antiviral lubricous composition formed by aprocess of the present invention has an osmolality that enables skin orepithelial tissue, particularly epithelial tissue within the vagina orrectum, to maintain a healthy plasma water-electrolyte balance. Infurther embodiments, the osmolality of the antiviral lubricouscompositions is less than about 1200 mOsmol/kg, including less thanabout 1000, 900, 800, 700, 600, 500, 400, 300, or 200 mOsmol/kg, down toless than about 100 mOsmol/kg. In even further embodiments, theosmolality of the antiviral lubricous composition is about 650 mOsmol/kgto about 800 mOsmol/kg. In other even further embodiments, theosmolality of the antiviral lubricous composition is isosmolal with thenormal osmolality of human semen, between about 250 mOsmol/kg and about380 mOsmol/kg. In still further embodiments, the osmolality of theantiviral lubricous composition is isosmolal with the normal osmolalityof vaginal secretions, between about 260 mOsmol and 290 mOsmol/kg.

In another embodiment, the mixing rotor type and mixing speed can beoptimized to control the viscosity of the resulting antiviral lubricouscomposition. In some embodiments, mixing can be conducted under shearconditions sufficient to homogenize the carrageenan-containingcomposition while preserving the length of each carrageenanpolysaccharide and maintaining their lubricity prior to applying thecomposition to the skin or epithelial tissue, particularly before or inconjunction with sexual activity. In even further embodiments, a paddlemixer is used for each of the mixing steps for forming the antivirallubricous composition. In other even further embodiments, each of themixing steps is conducted with low-speed mixer operating at a rotationalspeed of equal or less than about 500 revolutions per minute (RPM). Instill further embodiments, mixing of the antiviral lubricous compositionafter homogenizing the carrageenan within the aqueous solution can occurat speeds less than or equal to about 250 RPM.

In another embodiment, processes for forming the antiviral lubricouscomposition can further comprise several steps, including: (e) coolingthe homogenized antiviral lubricous composition until the temperature ofthe antiviral lubricous composition is less than about 30° C.; (f)mixing one or more pH-adjusting agents into the cooled antivirallubricous composition, at a weight sufficient to adjust the antivirallubricous composition to a pH of about 3.5 to about 7.0; (g) optionallymixing one or more sweeteners into the carrageenan suspension or thecooled antiviral lubricous composition, at up to 0.5% by weight of theantiviral lubricous composition; and (h) optionally mixing one or morepreservatives into the carrageenan suspension or the cooled antivirallubricous composition, at up to 1% by weight of the antiviral lubricouscomposition. In further embodiments, each of the additional components,such as the pH-adjusting agents, sweeteners, and preservatives describedabove, as well as salts and/or aromatic agents, can be included withinthe antiviral lubricant composition to supplement its anti-HPV activityand/or enhance its performance during sexual activity.

In another embodiment, antiviral lubricous compositions of the presentinvention can further comprise one or more pH-adjusting agentscomprising an acid, particularly an organic acid, and more particularlycitric acid. In other embodiments, the one or more pH-adjusting agentscan include a weak acid and its conjugate base to create a buffer. Inone non-limiting example, the addition of citrate to the antivirallubricous composition can be accomplished by adding both citric acid anda citrate salt, such as sodium or magnesium citrate.

In another embodiment, the pH of the antiviral lubricous composition isless than about 9.0, including less than about 8.0, 7.0, 6.5, 6.0, 5.5,5.0, 4.5, or 4.0, down to less than about 3.5. In other furtherembodiments, the pH of the antiviral lubricous composition is at leastabout 3.5, including at least about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0 or8.0, up to at least about 9.0. In even further embodiments, the pH ofthe antiviral lubricous composition is between about 5.5 and about 7.0.In still further embodiments, the pH of the antiviral lubricouscomposition can be optimized to be either applied to the vaginadirectly, or to contact the vagina during sexual activity. In suchembodiments, the pH of the antiviral lubricous composition is betweenabout 3.5 and about 5.5, particularly about 4.5.

In another embodiment, the pH of the antiviral lubricous composition isadjusted after the carrageenan has been homogenized and the resultingantiviral lubricous composition has been cooled. In further embodiments,the antiviral lubricous composition can be cooled to less than about 50°C., including less than about 45° C., 40° C., 35° C., 30° C., or 25° C.,down to less than about 20° C. In even further embodiments, theantiviral lubricous composition is cooled to less than about 30° C.before the pH of the composition is adjusted.

In another embodiment, the concentration of the one or more pH-adjustingagents within the pH-adjusted antiviral lubricous composition is lessthan about 1% by weight of the antiviral lubricous composition,including less than about 0.5%, 0.25%, 0.1%, or 0.05%, down to less thanabout 0.01% by weight of the antiviral lubricous composition. In furtherembodiments, the concentration of the one or more pH-adjusting agentswithin the pH-adjusted antiviral lubricous composition is equal or lessthan about 0.1% by weight. In even further embodiments, the weight ofthe one or more pH-adjusting agents within the pH-adjusted antivirallubricous composition is equal or less than about 0.05% by weight. ThepH-adjusting agents can be added into the composition as a component ofthe carrageenan powder to which the polyol is added, into thecarrageenan suspension, or into the antiviral lubricous compositionafter the carrageenan is homogenized.

In another embodiment, the antiviral lubricous compositions of thepresent invention can further comprise one or more sweeteners,particularly saccharin, comprising about 0.01% by weight to about 1% byweight of the antiviral lubricous composition, particularly about 0.1%to about 0.5% by weight of the antiviral lubricous composition. Infurther embodiments, the concentration of saccharin in the antivirallubricous composition is about 0.125% by weight. The sweetener can beadded into the composition as a component of the carrageenan powder towhich the polyol is added, into the carrageenan suspension, or into theantiviral lubricous composition after the carrageenan is homogenized.

In other embodiments, saccharin can be added to the carrageenan mixtureor the carrageenan suspension as an aliquot from a concentrated stocksolution. In further embodiments, the total weight of the saccharinstock solution added to the carrageenan mixture or the antivirallubricous composition comprises about 1% to about 10% by weight of thecompleted antiviral lubricous composition. In even further embodiments,the saccharin stock solution is a 2.5% by weight of saccharin in water.In still further embodiments, the amount of 2.5% by weight saccharinstock solution added to the carrageenan mixture is equal to about 5% byweight of the antiviral lubricous composition, wherein the finalconcentration of saccharin in the antiviral lubricous composition isabout 0.125% by weight. In even still further embodiments, the saccharinis provided as sodium saccharin.

In another embodiment, the antiviral lubricous compositions of thepresent invention can further comprise about 0.01% to about 1.0% byweight of one or more preservatives, particularly one or morepreservatives selected from the group consisting of 2-phenoxylethanol,chlorphenesin, and sodium dehydroacetate, including combinationsthereof. The preservative can be added into the composition as acomponent of the carrageenan powder to which the polyol is added, intothe carrageenan suspension, or into the antiviral lubricous compositionafter the carrageenan is homogenized.

In another embodiment, the antiviral lubricous compositions of thepresent invention can optionally further comprise one or more aromaticagents designed to provide a pleasing fragrant effect on thecomposition. Aromatic agents can include essential oils or componentcompounds within essential oils capable of imparting an odor.Non-limiting examples of fragrances that can be provided by sucharomatic agents include citrus, lemon, berry, or peppermint fragrances.In some embodiments, aromatic agents can comprise between about 0.01%and about 5% by weight of the antiviral lubricous composition,particularly between about 0.1% and about 2.5% by weight of theantiviral lubricous composition.

In another embodiment, the antiviral lubricous compositions of thepresent invention can further comprise a salt, particularly a sodiumsalt or a zinc salt, more particularly a zinc salt, that can be utilizedto increase the ionic strength of the composition while also supportingor complementing either or both of the rheological properties orantiviral activity of the composition. The salt can be added into thecomposition as a component of the carrageenan powder to which the polyolis added, into the carrageenan suspension, or into the antivirallubricous composition after the carrageenan is homogenized.

In another embodiment, processes to form homogenized antiviral lubricouscompositions of the present invention can be completed in less than 12hours, including less than 10, 8, 6, 4, or 3 hours, down to less than2.5 hours. In further embodiments, processes to form homogenizedantiviral lubricous compositions of the present invention are completedin 2 to 3 hours.

In another embodiment, the processes to form antiviral lubricouscompositions of the present invention can comprise the steps of: (a)providing a carrageenan powder comprising carrageenan, the carrageenancomprising at least about 90% by weight λ-carrageenan and up to about10% by weight ι-carrageenan; (b) mixing the carrageenan powder with apolyol, comprising agitating or stirring the carrageenan powder with thepolyol for a time sufficient to form a wet carrageenan mixture, whereinthe weight ratio of the glycol to the carrageenan is about 1:1 to about10:1; (c) dispersing the wet carrageenan mixture into an aqueoussolution under shear mixing for a time sufficient to form a turbidcarrageenan suspension, wherein the weight ratio of the aqueous solutionto the carrageenan is about 45:1 to about 8:1; (d) adding one or moresweeteners into the turbid carrageenan suspension, while agitating theturbid carrageenan suspension, wherein the sweetener comprises up to0.5% by weight of the completed antiviral lubricous composition; (e)heating the turbid carrageenan suspension up to a temperature of 70° C.and under shear mixing for a time sufficient, including up to 100minutes, to transform the turbid carrageenan suspension into a clarifiedhomogeneous solution, thereby forming the antiviral lubricouscomposition; (f) cooling the homogenized antiviral lubricous compositionuntil the temperature of the antiviral lubricous composition is lessthan about 30° C.; (g) adding, under agitation, one or more pH-adjustingagents into the cooled antiviral lubricous composition, at a weightsufficient to adjust the antiviral lubricous composition to a pH ofabout 3.5 to about 7.0, and (h) adding, under agitation, one or morepreservatives into the turbid carrageenan suspension or the cooledantiviral lubricous composition, at up to 1% by weight of the antivirallubricous composition; wherein (i) the antiviral lubricous compositioncomprises about 0.2% to about 2.3% by weight carrageenan, and up toabout 10% by weight polyol; (ii) the antiviral lubricous composition hasa viscosity of less than about 5,000 cP; (iii) the antiviral lubricouscomposition is translucent; and (iv) the antiviral lubricous compositionis effective in reducing, inhibiting, or ameliorating the transmissionof human papillomavirus (HPV). In further embodiments, the antivirallubricous composition comprises: about 1.5% to about 1.7% by weight ofthe carrageenan; about 4% to about 5% by weight of 1,2-propanediol; aviscosity of about 2,000 cP to about 3,000 cP; an osmolality of about650 mOsmol/kg to about 800 mOsmol/kg; and a pH of about 6.25 to about6.75. In even further embodiments, the carrageenan comprises about 90%by weight λ-carrageenan and about 10% by weight ι-carrageenan.

In another embodiment, processes to form antiviral lubricouscompositions of the present invention can comprise the steps of: (a)providing a carrageenan powder comprising carrageenan, the carrageenancomprising at least about 90% by weight λ-carrageenan and up to about10% by weight ι-carrageenan; (b) combining, while mixing, thecarrageenan powder with an aqueous solution comprising a polyol to forma turbid carrageenan suspension; and (c) heating the turbid carrageenansuspension up to a temperature of at least 60° C. and mixing for a timesufficient to transform the turbid carrageenan suspension into aclarified homogeneous solution, thereby forming the antiviral lubricouscomposition; wherein (i) the antiviral lubricous composition comprisesabout 0.5% to about 2.3% by weight carrageenan, and up to about 10% byweight polyol; (ii) the antiviral lubricous composition has a viscosityof less than about 5,000 cP; (iii) the antiviral lubricous compositionhas an osmolality of less than about 1,200 mOsmol/kg; (iv) the antivirallubricous composition is translucent; (v) the antiviral lubricouscomposition has a turbidity that is less than or equal to about 5.0 NTU;(vi) the pH of the antiviral lubricous composition is about 3.5 to about7.0; and (vii) the antiviral lubricous composition is effective inreducing, inhibiting, or ameliorating the transmission of humanpapillomavirus (HPV). In some embodiments, the polyol is propyleneglycol.

In another embodiment, a device for performing a mixing step of thepresent invention, including a step of agitating or a step ofdispersing, can comprise any conventional mixing apparatus for theintended use. One non-limiting example of a mixing apparatus is a paddlemixer. One example of a paddle mixer is a mixer that comprises at leastone folding impeller blade. One specific example of a paddle mixer is aMixer Direct R-AD665 industrial gallon paddle mixer with two foldingimpeller blades.

In another embodiment, the antiviral lubricous composition can becontacted with the skin or epithelial tissue, particularly skin orepithelial tissue located on or within at least one of the vagina, anus,mouth, or penis, of one or more of the sexual partners prior to sexualactivity, in order to prophylactically inhibit the transmission of HPVfrom one sexual partner to another. In such embodiments, the antivirallubricous composition can be contacted with the skin of one or more ofthe sexual partners less than about 8 hours, 4 hours, 2 hours, 1 hour,30 minutes, 15 minutes, 5 minutes, 1 minute, or about 30 seconds priorto sexual activity, down to less than about 1 second prior to sexualactivity. In other embodiments, the antiviral lubricous composition canbe contacted with the skin or epithelial tissue, particularly skin orepithelial tissue located on or within at least one of the vagina, anus,mouth, or penis, of one or more of the sexual partners after sexualactivity, in order to reduce the spread of HPV from cell to cell afterHPV has been transmitted. In such embodiments, the antiviral lubricouscomposition can be contacted with the skin or epithelial tissue of oneor more of the sexual partners less than about 8 hours, 4 hours, 2hours, 1 hour, 30 minutes, 15 minutes, 5 minutes, 1 minute, or about 30seconds after sexual activity, down to less than about 1 second aftersexual activity.

In another embodiment, carrageenan powders can include other ratios ofλ- to κ- and/or ι-forms of carrageenan relative to each other. In someembodiments, λ-carrageenan comprises at least about 50% by weight of thecarrageenan powder, including at least about 60 or 70% by weight, up toabout 80% by weight of the carrageenan powder. In other embodiments,λ-carrageenan comprises less than about 85, 80, or 70% by weight, downto less than about 60% by weight of the carrageenan powder. Within suchembodiments, the amount of κ- and ι-carrageenans can increase such thatwhen present, κ-carrageenan and ι-carrageenan together comprise up toabout 50% by weight of the carrageenan powder, including up to 40%, 30%,or up to 20% by weight of the carrageenan powder.

In another embodiment, the present invention also provides methods forreducing, inhibiting, or ameliorating the transmission of HPV betweentwo or more partners engaging in sexual activity. In some embodiments,methods according to the present invention comprise the steps of: (a)providing any of the above-described antiviral lubricous compositions,and (b) contacting the antiviral lubricous composition with the skin orepithelial tissue of one or more of the partners, wherein the skin orepithelial tissue located on or within at least one of the vagina, anus,mouth, or penis. In further embodiments, at least one partner is maleand at least one partner is female. In other further embodiments, atleast two partners are male. In still other further embodiments, atleast two partners are female. In yet other further embodiments, thereare three or more sexual partners, comprising any combination of men orwomen.

In another embodiment, methods for reducing, inhibiting, ameliorating,or preventing the transmission of HPV between partners engaging insexual activity comprise the steps of: (a) providing a substratecomprising one or more skin-contacting surfaces, wherein the substrateis configured for insertion into one or more body cavities selected fromthe group consisting of the vagina, mouth, or anus; (b) lubricating oneor more of the skin-contacting surfaces of the substrate with theantiviral lubricous composition, thereby producing a lubricatedsubstrate; (c) contacting the lubricated substrate with the skin orepithelial tissue located on or within at least one of the vagina, anus,mouth, or penis of one or more of the partners; and (d) transferring theantiviral lubricous composition from the lubricated substrate to theskin or epithelial tissue.

In another embodiment, the substrate is a condom. In furtherembodiments, the condom comprises latex. In other further embodiments,the condom comprises polyurethane and/or other synthetic materials. Instill other further embodiments, the condom is incompatible withoil-based personal lubricants. In yet still other further embodiments,the condom is selected from the group consisting of a male condom and afemale condom.

In some embodiments in which a condom is a substrate, methods forreducing, inhibiting, ameliorating, or preventing the transmission ofHPV between partners engaging in sexual activity further comprise thesteps of: (g) lubricating a skin-contacting surface of a condom; (h)contacting the skin or epithelial tissue within mouth, vagina, or anusof one or more of the partners with the lubricated skin-contactingsurface of the condom; and (i) transferring the antiviral lubricouscomposition from the lubricated skin-contacting surface of the condom tothe skin or epithelial tissue.

In another embodiment in which a condom is a substrate, methods forreducing, inhibiting, ameliorating, or preventing the transmission ofHPV between partners engaging in sexual activity further comprise thesteps of: (g) placing a condom over the finger or penis of one partner;(h) lubricating an external surface of the condom with the antivirallubricous composition; (i) contacting the skin or epithelial tissuewithin the mouth, vagina, or anus of one or more additional partnersusing the lubricated external surface of the condom; and (j)transferring the antiviral lubricous composition from the lubricatedexternal surface of the condom to the skin or epithelial tissue.

In other embodiments in which a condom is a substrate, methods forreducing, inhibiting, ameliorating, or preventing the transmission ofHPV between partners engaging in sexual activity further comprise thesteps of: (g) lubricating the condom; (h) sealing the lubricated condomwithin a packaging; (i) storing the lubricated condom within thepackaging; (j) removing the lubricated condom from the packaging; (k)applying the lubricated condom to the finger or penis of one of thesexual partners; (l) contacting the skin or epithelial tissue within themouth, vagina, or anus of one or more additional partners using thelubricated condom; and (m) transferring the antiviral lubricouscomposition from the lubricated condom to the skin or epithelial tissue.

In another embodiment, the substrate is a sexual accessory deviceincluding but not limited to sex toys, dildos, vibrators, rings, orbeads. In further embodiments, the method further comprises the steps ofsealing the lubricated sexual accessory device within a packaging,storing the lubricated sexual accessory device within the packaging, andremoving the lubricated sexual accessory device from the packaging priorto contacting the skin or epithelial tissue of one or more of thepartners. The antiviral lubricous composition can be applied to anyskin-contacting surface of the sexual accessory device, typically priorto contact with the skin of one or more the sexual partners,particularly prior to insertion into the vagina, anus, or mouth.

In another embodiment, a condom lubricated by any of the antivirallubricous compositions of the present invention can be applied to anunlubricated sexual accessory device to provide lubricity for use duringsexual activity. In other embodiments, an unlubricated condom can beapplied to a sexual accessory device lubricated by any of the antivirallubricous compositions of the present invention. In still otherembodiments, an unlubricated condom can be applied to an unlubricatedsexual accessory device and subsequently be lubricated by any of theantiviral lubricous compositions of the present invention.

In another embodiment, the substrate is an internal applicatorconfigured for insertion into the vagina or rectum, and wherein theinternal applicator is selected from the group consisting of a swab, anelongate stick or rod, a wearable insert, an injector, a syringe, acannula, or a pipette. In further embodiments, the internal applicatorcomprises a skin-contacting surface that is configured to contactepithelial tissue within a person's body cavity, particularly within thevagina or rectum. In other further embodiments, the internal applicatorcomprises a container configured for housing or containing the antivirallubricous composition prior to transferring the antiviral lubricouscomposition onto epithelial tissue within a person's body cavity,particularly the vagina or rectum.

The present invention also provides kits for reducing, inhibiting, orameliorating the transmission of HPV between partners engaging in sexualactivity, the kit comprising any of the above-described antivirallubricous compositions and instructions describing any of the methodsdisclosed above for contacting the antiviral lubricous composition withthe skin of one or more of the partners. The kit can further compriseany of the above-described substrates, including condoms, sexualaccessory devices, and/or internal applicators.

These and other embodiments of the present invention will be apparent toone of ordinary skill in the art from the following detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a plot of the viscosity of antiviral lubricous compositionsas a function of the concentration of carrageenan.

FIG. 2 shows a plot of the osmolality of antiviral lubricouscompositions as a function of 1,2-propanediol concentration.

DETAILED DESCRIPTION OF THE INVENTION

It should be understood that while reference is made to exemplaryembodiments and specific language is used to describe them, nolimitation of the scope of the invention is intended. Furthermodifications of the methods described herein, as well as additionalapplications of the principles of those inventions as described, whichwould occur to one skilled in the relevant art and having possession ofthis disclosure, are to be considered within the scope of thisinvention. Furthermore, unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which embodiments ofthis particular invention pertain. The terminology used is for thepurpose of describing those embodiments only, and the terminology is notintended to be limiting unless specified as such. Headings are providedfor convenience only and are not to be construed to limit the inventionin any way. Additionally, throughout the specification and claims, agiven chemical formula or name shall encompass all optical isomers andstereoisomers, as well as racemic mixtures where such isomers andmixtures exist.

The present disclosure includes aqueous compositions that are activeagainst human papillomavirus (HPV) in vivo, and which can be utilized aspersonal lubricants during sexual activity. The antiviral lubricouscompositions can be contacted with the skin or epithelial tissueanywhere an HPV infection is known to be present, or in areas that arecommonly lubricated during sexual activity, including but not limited tothe vagina, anus, penis, and mouth. The antiviral lubricous compositionsare capable of reducing, inhibiting, ameliorating, or preventing thetransmission and/or the persistence of HPV between sexual partners,including male-female, male-male, and female-female sexual partnerships.

λ-Carrageenan-Containing Compositions

The anti-HPV activity of the antiviral lubricous compositions of thepresent invention results from the presence of carrageenan, particularlyλ-carrageenan. Carrageenan is a generic term for a broad family ofnaturally occurring sulfated polysaccharides that are extracted from awide range of species of seaweed algae, particularly from Chondruscrispus, a red seaweed found on the Atlantic coast of the United States.Extracted carrageenans can typically be obtained in one of ten forms,which differ in terms of sulfation content, sulfation location withineach polysaccharide, and acid/base character. Three of theforms—κ-carrageenan, ι-carrageenan, and λ-carrageenan—are particularlycommon within compositions used in the food and pharmaceuticalindustries. The structures of κ-carrageenan, ι-carrageenan, andλ-carrageenan are shown below:

As shown above, κ-carrageenan, ι-carrageenan, and λ-carrageenan compriserepeating galactose units. In particular, κ-carrageenan andι-carrageenan comprise alternating units of D-galactose and3,6-anhydro-galactose (3,6-AG), whereas λ-carrageenan does not compriseany 3,6-AG. Each form differs in the number of sulfate groups perdisaccharide, where κ-carrageenan, ι-carrageenan, and λ-carrageenancomprise one, two, or three sulfate groups, respectively, peralternating unit. As the number of sulfate groups within thepolysaccharides increase, the ability of particular forms of carrageenanto produce gels decreases. Similarly, all of the κ-, ι-, and λ-forms ofcarrageenan have the ability to solubilize in aqueous solution, althoughthe temperature at which a particular form will solubilize is also afunction of relative sulfate content. Thus, a pure sample ofλ-carrageenan can be solubilized within water at a lower temperaturethan a pure sample of κ-carrageenan.

Carrageenans are commonly used in the food and pharmaceutical industryas thickening agents and/or gelation agents. As carrageenans arehydrated within an aqueous composition, they begin to swell, raising theviscosity of the composition exponentially as a function of the totalcarrageenan concentration. However, the rate of exponential growth isinversely proportional to the sulfate content within each form ofcarrageenan, so κ-carrageenan causes a greater exponential growth inviscosity than ι-carrageenan, which itself has a greater effect onviscosity than λ-carrageenan. Furthermore, heated compositionscomprising κ-carrageenan and ι-carrageenan are able to form gel networksupon cooling, as the polysaccharides form double-helical,quasi-crystalline networks, particularly in the presence of cations.However, the presence of λ-carrageenan within a composition partiallyinhibits the formation of a gel, and in compositions where theλ-carrageenan is the most abundant, gel formation is pre-emptedcompletely. Without being limited by a particular theory, it is believedthat the lack of a 3,6-AG group within λ-carrageenan drives gelinhibition.

Although the relative effects of κ-, ι-, λ-forms of carrageenan on theviscosity of a composition are known, the rate of exponential growth ofviscosity is generally not predictable from one composition to another,especially where the ratio of κ-, ι-, and λ-carrageenans differ betweencompositions. Additionally, the methods in which the carrageenans andother components are processed also have a dramatic effect on theviscosity of the resulting composition. Factors relevant in theviscosity of the final product include, but are not limited to: heatingtemperature(s), shear conditions, rotor type, mixing speed, mixingtimes, and additional components that are also added to the composition.Consequently, the viscosity as a function of total carrageenanconcentration can only be modeled where the ratio of each form ofcarrageenan is constant, and the processing steps are otherwiseidentical.

While carrageenan compositions that predominantly contain κ- and ι-formsof carrageenan are useful for thickening compositions or gels, they areinactive against HPV. The λ-carrageenan form, on the other hand, hasbeen shown to be active against HPV both in vitro (see Buck, et al.,above) and in vivo. Several patents and patent publications similarlydiscuss the use of carrageenan within medicaments as an antimicrobial orantiviral compound (see U.S. Pat. Nos. 5,208,031 and 8,367,098, and U.S.Pat. Pubs. 2005/0171053, 2005/0239742, 2005/0261240, 2006/0127340,2008/0227749, 2009/0088405, and 2011/0229446, the disclosures of whichare incorporated by reference in their entireties). Without being boundby any particular theory, λ-carrageenan utilizes a “lock and key” typemechanism by which the polysaccharide attracts the HPV virus, interactswith viral capsid, and then completely arrests, prevents the replicationof the HPV virus, and further inhibits HPV viral activity. This resultsin significant reduction of the transmission and persistence of the HPVvirus in sexually active men and women.

In one study, a λ-carrageenan-containing gel was given tosexually-active women that were at high risk of contracting and/ortransmitting HPV during sexual activity (see Marais, D., et al., (2011)Antiviral Therapy 16:1219-1226, as well as U.S. Pat. No. 8,367,098, thedisclosures of which are incorporated by reference in their entireties).The tested composition, Carraguard®, comprises a 3% by weight mixture ofκ-carrageenan and λ-carrageenan, and has a viscosity of between 30,000and 40,000 cP. Study participants were instructed to apply the gel inconjunction with vaginal intercourse. Over the three-year period of thestudy, the authors determined that of the women with “relatively highadherence to gel use,” women who were given the λ-carrageenan-containinggel were only 62% as likely to be classified as HPV positive, relativeto the placebo group.

As described above, however, carrageenans (of any form) havehistorically been used as thickening agents and generally are notpreferred in personal lubricant formulations because they cause anexponential increase in the viscosity of the composition. In particular,gel compositions comprising κ-carrageenan and/or large amounts ofι-carrageenan are typically very viscous and tend to dry out quicklyonce applied to the skin or epithelial tissue, causing them to formsticky residues and lose their lubricity. As a result, most topicalcarrageenan-containing compositions, including the one studied inMarais, et al. as well as the related composition in U.S. Pat. No.8,367,098, are typically gels or creams. To put the viscosity of thesecarrageenan-containing compositions into context, the viscosity ofCarraguard® compared to several common compositions is shown in Table 1,below.

TABLE 1 Approximate Viscosities of Common Materials at Room TemperatureMaterial Viscosity in Centipoise Water 1 cP Milk 3 cP SAE 10 Motor Oil85-140 cP SAE 20 Motor Oil 140-420 cP SAE 30 Motor Oil 420-650 cP SAE 40Motor Oil 650-900 cP Castrol Oil 1,000 cP Karo Syrup 5,000 cP Honey10,000 cP Chocolate 25,000 cP Carraguard ® 30,000-40,000 cP Ketchup50,000 cP Mustard 70,000 cP Sour Cream 100,000 cP

As illustrated in Table 1, the viscosity of the Carraguard® gel utilizedin the Marais study is in a range between the viscosity of chocolate andthe viscosity of ketchup. Although chocolate and ketchup both haveshear-thinning properties, and chocolate in particular can compriseedible compositions that can be utilized during sexual activity, thehigh viscosity of both compositions causes them to perform poorly aspersonal and sexual lubricants.

In contrast, compositions that are commonly used as personal lubricantsand don't contain carrageenan are typically five to ten times lessviscous than the gels used in the Marais study and described in the '098patent. Ideally, a personal lubricant composition should have aviscosity such that it can be poured or lightly squeezed from itscontainer, remain on the skin after being applied, and undergo shearthinning in response to a stress, such as during sexual activity.Materials commonly found in personal lubricants include, but are notlimited to: oils, particularly silicone oils, gums, celluloses,glycerins, polyols, glycols, glycans, polyquaterniums, and otherpolymers. However, while these lubricants do provide pleasing resultsduring sexual activity, they do not provide any protection against HPV.

Another human in vivo study (see Magnan, et al., above) did explore theuse of a less viscous personal composition containing λ-carrageenan foranti-HPV activity. Similar to the Marais study above, women wererandomly assigned a placebo or a commercial composition, Divine 9®, thatcomprises λ-carrageenan, and were told to apply the composition inconjunction with sexual activity. The test composition comprised 1.4% byweight of a carrageenan mixture comprising λ-carrageenan andι-carrageenan, 37% by weight of propylene glycol, and a viscositybetween 1,000 and 4,000 cP (see Example 1, below). Although the Magnanstudy showed a similar reduction in HPV incidence as the Marais study,the presence of such a high concentration of propylene glycol caused thecomposition to have an osmolality of over 5,000 mOsm/kg, a level that ispotentially dangerous to people who use the composition and which may,for some people, increase the possibility of contracting HPV.

According to results presented in a World Health Organization (WHO)report on sexual health (see “Use and Procurement of AdditionalLubricants for Male and Female Condoms: WHO/UNFPA/FHI360 Advisory Note”World Health Organization, Geneva Switzerland, (2012), incorporated byreference in its entirety), research suggests that lubricants with highosmolality might cause vaginal and anal epithelial damage, which couldin turn increase the risk of infection by HPV, HIV, and other sexuallytransmitted infections. The WHO also found that the primary factor thatdetermines the osmolality of a given personal lubricant is the presenceof glycols within the composition. Glycols, also commonly known as“polyols,” most commonly comprise glycerol, 1,2-propanediol, and1,3-propanediol, and can upset the water-electrolyte balance withinepithelial cells. The WHO goes on to show that most of the commerciallyavailable lubricants have osmolalities that far exceed the osmolality ofnormal vaginal secretions (260-290 mOsmol/kg) and semen (250-380mOsmol/kg), and recommends that companies tailor the osmolality of theirmarketed personal lubricant compositions to be under 1,200 mOsmol/kg,with a goal of being as isosmolal as possible with vaginal secretionsand/or semen (between 250 and 400 mOsmol/kg).

Antiviral Lubricous Compositions of the Present Invention

The present invention provides several novel antiviral lubricouscompositions that comprise λ-carrageenan, are active against HPV, andhave a viscosity similar to commonly-available lubricants that do notcontain carrageenan. In another embodiment, the antiviral lubricouscompositions possess a rheological profile that enable to compositionsto retain their moisture and lubricity for several hours upon beingapplied, and which provide a pleasing experience to people engaging insexual activity. In further embodiments, the antiviral lubricantcompositions are pseudoplastic, non-Newtonian fluid compositions thatundergo shear thinning in response to mechanical strain, particularlyduring sexual activity. In even further embodiments, antiviral lubricantcompositions of the present invention can be poured directly from acontainer, without having to be squeezed or otherwise manually extractedfrom the container. In other even further embodiments, the antivirallubricous composition is substantially free of a gel network.

As described above, carrageenans of all types can be obtained from seaalgae extracts, typically as a mixture of two, three, or more forms ofcarrageenan. Carrageenan mixtures can be obtained as raw extracts, orthey can be obtained as powders. In further embodiments, carrageenansutilized within antiviral lubricous composition are obtained as acarrageenan powder. Non-limiting examples of commercially-availablecarrageenan powders include Viscarin® PC 109, Viscarin® PC 209,Viscarin® PC 515, Gelcarin® PC 379, and Gelcarin® PC 911. In evenfurther embodiments, the carrageenan powder is Viscarin® PC 209.

In another embodiment, the carrageenan powder comprises at least about85% by weight λ-carrageenan, including at least about 90% by weight ofλ-carrageenan.

In another embodiment, κ-carrageenan and ι-carrageenan together cancomprise up to about 10% by weight of the carrageenan powder includingup to about 8%, 6%, 4%, 2%, or up to about 1% by weight of thecarrageenan powder. In other embodiments, when present, κ-carrageenanand ι-carrageenan together comprise at least about 1% by weight of thecarrageenan powder, including at least about 2%, 4%, or 6% by weight, upto at least about 8% by weight of the carrageenan powder. In evenfurther embodiments, κ-carrageenan and ι-carrageenan together compriseabout 1% to about 15% by weight of the carrageenan powder.

In another embodiment, the carrageenan powder comprises at least about90% by weight λ-carrageenan and up to about 10% by weight ι-carrageenan.In further embodiments, the carrageenan powder comprises about 90% byweight λ-carrageenan and about 10% by weight ι-carrageenan.

In another embodiment, carrageenan mixtures comprising λ-carrageenan aresubstantially homogenized within the antiviral lubricous composition,wherein a majority of the carrageenan polysaccharides within thecomposition are present as free molecules within an aqueous solvent. Infurther embodiments, the carrageenan mixtures are fully homogenizedwithin the antiviral lubricous composition. In some even furtherembodiments, homogeneous antiviral lubricous compositions have asubstantially uniform appearance and density. In other even furtherembodiments, the antiviral lubricous composition is a solution in whichthe ratio of carrageenan to the solvent is substantially uniform. Instill other even further embodiments, the antiviral lubricouscomposition is substantially free of particulates, aggregates, clumps,or other solids that are visible either to the naked eye and/or under10× magnification under a microscope. In still further embodiments, theantiviral lubricous composition is translucent. In even still furtherembodiments, the antiviral lubricous composition is transparent.

In another embodiment, carrageenan comprises at least about 0.001% byweight of the antiviral lubricous composition, including at least about0.01, 0.1, 0.5, 1, 2, 2.5, or 3% by weight, up to at least about 5% byweight of the antiviral lubricous composition. In further embodiments,carrageenan comprises 0.5% to about 2.3% by weight of the antivirallubricous composition. In even further embodiments, carrageenancomprises 0.8% to about 2.0% by weight of the antiviral composition. Instill further embodiments, carrageenan comprises 1.5% to about 1.7% byweight of the antiviral lubricous composition.

Similarly, the viscosity, rheology, sensation, and overall performanceof the λ-carrageenan-containing, antiviral lubricous composition can becontrolled by the addition of a minor concentration of a polymer,particularly a polyol, to the antiviral lubricous composition. Asdescribed above, polyols are one class of compounds that are commonlyfound in commercially-available personal lubricant products. Althoughpolyols are typically added to enhance the solubility of other polymersthat might be present in commercial products, polyols can also be addedin small quantities to antiviral lubricous compositions of the presentinvention to decrease the viscosity, provide a secondary source oflubricity, and/or to provide a stimulating “warming” or “tingling”feeling that is often pleasing to the user during sexual activity.Non-limiting examples of polyols that can be added can include glycerol,1,2-propanediol (propylene glycol), 1,3-propanediol, polyethyleneglycol, and polypropylene glycol, including combinations thereof. Insome embodiments, the polyol is a short-chain, non-polymeric compoundsuch as 1,2-propanediol or 1,3-propanediol. In some embodiments, thepolyol is propylene glycol.

In another embodiment, the polyol can comprise less than about 50% byweight of the antiviral lubricous composition, including less than about25, 15, 10, 9, 8, 7, 6, 5, 4, 3, or 2% by weight, down to less thanabout 1% by weight of the antiviral lubricous composition. In otherfurther embodiments, the antiviral lubricous composition comprises atleast about 1% by weight of the polyol, including at least about 2, 3,4, 5, 6, 7, 8, 9, 10, 15, or 25% by weight, including at least about 35%by weight. In even further embodiments, the polyol comprises about toabout 10% by weight of the antiviral lubricous composition.

In another embodiment, the polyol is propylene glycol (1,2-propanediol).In further embodiments, the antiviral lubricous composition comprises upto 8% by weight of propylene glycol. In even further embodiments, theantiviral lubricous composition comprises 0.5% to about 5% by weight ofpropylene glycol. In still further embodiments, the antiviral lubricouscomposition comprises about 4% to about 5% by weight of propyleneglycol. In some embodiments, the antiviral lubricous compositioncomprises between about 4.0% and about 4.5% by weight of propyleneglycol. In yet still further embodiments, the antiviral lubricouscomposition comprises between about 2.0% and about 2.5% by weight ofpropylene glycol.

In another embodiment, the presence of a polyol results an antivirallubricous composition that is superior to known personal lubricantcompositions because it maintains all of the sexual performance benefitsof the commercially-available personal lubricants, while also having theability to inhibit the transmission and/or persistence of HPV.Additionally, the antiviral lubricous compositions are thin enough toprovide the tactile benefits of a personal lubricant composition, whilealso thick enough to remain on the skin or epithelial tissue,particularly the vagina, anus, penis, or mouth prior to initiatingsexual contact. In some embodiments, the personal lubricant compositionhas a viscosity of less than about 10,000 cP, including less than about8,000, 6,000, 4,000, or 2,000 cP, down to less than about 1,000 cP. Inother embodiments, the antiviral lubricous composition has a viscosityof at least about 500 cP, including at least about 1,000, 2,000, 4,000,or 6,000 cP, up to at least about 8,000 cP. In further embodiments, theantiviral lubricous composition has a viscosity of about 500 cP to about8,000 cP, particularly about 1,000 cP to about 4,000 cP, and moreparticularly about 2,000 cP to about 3,000 cP. In some embodiments, theantiviral lubricous composition has a viscosity between about 1,500 cPand 2,500 cP. In some embodiments, the antiviral lubricous compositionhas a viscosity of about 2,000 cP.

In another embodiment, the amount of polyol within the antivirallubricous composition is limited, in order to provide an osmolality thatis within WHO-recommended levels. In other embodiments, the antivirallubricous composition has an osmolality that is less than about 1,200mOsm/kg, including less than about 1000, 900, 800, 700, 600, 500, 400,300, or 200 mOsmol/kg, down to less than about 100 mOsmol/kg. In furtherembodiments, the osmolality of the antiviral lubricous composition isabout 250 to about 800 mOsmol/kg.

In another embodiment, the osmolality of the antiviral lubricouscomposition is isosmolal with the osmolality of human plasma. In furtherembodiments, the antiviral lubricous composition is isosmolal withsemen. In other further embodiments, the antiviral lubricous compositionis isosmolal with vaginal secretions. In still other furtherembodiments, the osmolality of the antiviral lubricous composition isabout 250 mOsmol/kg to about 400 mOsmol/kg.

Additionally, and in another embodiment, several supplemental componentscan be added to the antiviral lubricous composition to complement theantiviral activity of the composition and/or to enhance thecomposition's performance during sex. In some embodiments, the pH of theantiviral lubricous composition can be controlled by the addition of apH-adjusting agent. Typically, the pH of the composition oncecarrageenan is solubilized into water is around 7 to 9. However, theeffectiveness of the antiviral lubricous composition can be supplementedby controlling the pH of the composition to either match or be similarto the target surface to which the composition is applied. For instance,the pH of a healthy vagina typically ranges from about 3.5 to about 5.5,whereas the pH of other epithelial cells, including those located withinthe rectum, is closer to a neutral pH. Thus, in some embodiments, thepH-adjusting agent is an acid that is capable of reducing the pH to arange that is complementary to the intended epithelial surface,particularly below a pH of about 8.0, including less than about 7.0,6.5, 6.0, 5.5, 5.0, 4.5, or 4.0, down to less than about 3.5. In otherembodiments, the pH of the antiviral lubricous composition is at leastabout 3.5, including at least about 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or7.0, up to at least about 8.0. In further embodiments, the pH of theantiviral lubricous composition is about 3.5 to about 5.5, particularlyabout 4.5. In other further embodiments, the pH of the antivirallubricous composition is about 5.5 to about 7.0. In still other furtherembodiments, the pH of the antiviral lubricous composition is about 6.25to about 6.75.

In some embodiments, the pH-adjusting agent is a strong acid, including,but not limited to, hydrochloric acid or sulfuric acid. However, inother embodiments, the pH-adjusting agent is a weak acid, in order tocreate a buffered antiviral lubricous composition. Weak acids can beselected based on their buffering capacity, pKa, and availability.Non-limiting examples of weak acids that can be utilized as pH-adjustingagents can include citric acid, lactic acid, and acetic acid. In furtherembodiments, the antiviral lubricous composition comprises between about0.01% and about 1.0% by weight of a pH-adjusting agent, particularlybetween about 0.04% and about 0.06% by weight of the pH-adjusting agent.In even further embodiments, the pH-adjusting agent is citric acid.

In some embodiments, the antiviral lubricous composition can optionallyfurther comprise one or more preservatives, which can be added toprevent microbial growth within the antiviral lubricous compositionduring storage. Any one or more of several preservatives may be selectedfrom preservatives known to those of skilled in the art, including butnot limiting to one or more of the following: methylparaben, benzoicacid, salicylic acid, sorbic acid, propylparaben, and sodiumdehydroacetate, including combinations thereof. The preservative may bepresent in the compositions of this invention in an amount of up toabout 1% by weight of the composition.

In some embodiments, the antiviral lubricous composition can optionallyfurther comprise one or more sweeteners that enhance the flavor thecomposition when it comes in contact with a person's mouth. In someembodiments, the sweetener is an artificial sweetener, the presence ofwhich can also inhibit bacterial growth within the antiviral lubricouscomposition during storage. Non-limiting examples of artificialsweeteners include, but are not limited to aspartame, saccharin,sucralose, neotame, and acesulfame potassium. In further embodiments,the sweetener is saccharin. In even further embodiments, the antivirallubricous composition further comprises up to about 0.005% by weight ofsaccharin. In still further embodiments, the antiviral lubricouscomposition comprises about 0.125% saccharin.

In addition to or in lieu of sweeteners, the antiviral lubricouscomposition can optionally further comprise other aromatic agents orfragrances that can mask either the scent of the composition itself orthe skin or epithelial tissue to which the antiviral lubricouscomposition is applied. Non-limiting examples of such fragrances includevanilla, lavender, oregano, thyme, lemongrass, lemons, oranges, anise,cloves, aniseed, cinnamon, geraniums, roses, mint, peppermint,citronella, eucalyptus, sandalwood, cedar, rosmarin, pine, vervainfleagrass, or ratanhiae, including combinations thereof, although anyessential oil-based fragrance can be chosen. In other embodiments, theantiviral lubricous composition can optionally further comprise one ormore chemical, aroma-causing compounds that cause the odor or fragrancewithin an essential oil-based fragrance. Non-limiting examples ofchemical, aroma-causing compounds that can be comprised in any of theantiviral lubricous compositions include carvacrol, eugenol, linalool,thymol, p-cymene, myrcene, borneol, camphor, caryophillin,cinnamaldehyde, geraniol, nerol, citronellol, and menthol, includingcombinations thereof.

In some embodiments, the antiviral lubricous composition can optionallyfurther comprise one or more metal salts. The addition of a metal saltcan have several effects, including controlling the ionic strength ofthe composition, enhancing its antimicrobial or antiviral activity, oradding in the solubilization of one or more components. Metal salts thatcan be added include, but are not limited to, zinc, silver, copper,alkali, or alkaline earth metal salts. In further embodiments, the metalsalt is a zinc salt or a sodium salt.

In some embodiments, the antiviral lubricous composition can optionallyfurther comprise one or more pharmaceutical antiviral, antifungal, orantimicrobial compounds.

Further, the present invention also provides several methods forreducing, inhibiting, or ameliorating the transmission of HPV betweentwo or more partners engaging in sexual activity, using the antivirallubricous compositions made by the processes described below. In a firstembodiment, the method comprises the step of contacting the antivirallubricous composition with the skin or epithelial tissue of one or moreof the partners, wherein the skin or epithelial tissue located on orwithin at least one of the vagina, anus, mouth, or penis. As usedherein, the term “vagina” includes skin or epithelial tissue locatedwithin the vagina itself and/or surrounding the vagina, including butnot limited to the vulva, labia, clitoris, vaginal opening, and thecervix. In further embodiments, at least one partner is male and atleast one partner is female. In other further embodiments, at least twopartners are male. In still other further embodiments, at least twopartners are female.

In another embodiment, the antiviral lubricous composition can becontacted with the skin, particularly skin located on or within at leastone of the vagina, anus, mouth, or penis, of one or more of the sexualpartners prior to sexual activity, in order to prophylactically inhibitthe transmission of HPV from one sexual partner to another. In suchembodiments, the antiviral lubricous composition can be contacted withthe skin of one or more of the sexual partners less than about 8 hours,4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, 5 minutes, 1 minute,or about 30 seconds prior to sexual activity, down to less than about 1second prior to sexual activity. In other embodiments, the antivirallubricous composition can be contacted with the skin of one or more ofthe sexual partners at least about 30 seconds, 1 minute, 5 minutes, 15minutes, 30 minutes, 1 hour, 2 hours, 4 hours, or about 8 hours prior tosexual activity.

In another embodiment, the antiviral lubricous composition can becontacted with the skin, particularly skin located on or within at leastone of the vagina, anus, mouth, or penis, of one or more of the sexualpartners after sexual activity, in order to reduce the spread of HPVfrom cell to cell after HPV has been transmitted through skin-to-skincontact. In such embodiments, the antiviral lubricous composition can becontacted with the skin of one or more of the sexual partners less thanabout 8 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, 5minutes, 1 minute, or about 30 seconds after sexual activity, down toless than about 1 second after sexual activity. In other embodiments,the antiviral lubricous composition can be contacted with the skin ofone or more of the sexual partners at least about 30 seconds, 1 minute,5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, or about 8hours after sexual activity.

In another embodiment, methods for reducing, inhibiting, or amelioratingthe transmission of HPV between two or more partners engaging in sexualactivity further comprise the steps of providing a substrate comprisingone or more skin-contacting surfaces, wherein the substrate isconfigured for insertion into one or more body cavities selected fromthe group consisting of the vagina, mouth, or anus; lubricating one ormore of the skin-contacting surfaces of the substrate with the antivirallubricous composition, thereby producing a lubricated substrate;contacting the lubricated substrate with the skin or epithelial tissuelocated on or within at least one of the vagina, anus, mouth, or penisof one or more of the partners; and transferring the antiviral lubricouscomposition from the lubricated substrate to the skin or epithelialtissue. In some further embodiments, there is only a single person,either a man or a woman, using the substrate during sexual activity. Inother further embodiments, there are two or more partners using thesubstrate, wherein any of the sexual partners can be either a man or awoman.

Substrates suitable for use in conjunction with methods of the presentinvention include any object, device, or accessory that can be used tocontact internal or external surfaces on or within the vagina, anus,mouth, or penis during sexual activity. Non-limiting examples ofsubstrates that can be utilized in accordance with methods of thepresent invention include condoms; sexual accessory devices such as sextoys, dildos, vibrators, rings, and beads; and internal applicators;comprising materials including but not limited to rubber, latex,plastic, wood, and/or metal. Such examples are described in U.S. Pat.Nos. 6,983,751 and 9,119,763; U.S. Design Pat. No. D599,486, and U.S.Patent Publication 2006/0178602, the disclosures of which are includedby reference in their entireties. Those skilled in the art wouldunderstand that there are countless other examples of substrates, bothcommercially available and improvised, sexually-themed or not, which canbe utilized during sexual activity and to which antiviral lubricouscompositions of the present invention can be applied.

In another embodiment, the substrate is a condom. As used in thisapplication, the term “condom,” includes devices designed to be worn byeither a male or female, within or on the penis, vagina, anus, orfinger. Condoms can also be applied over sexual accessory devices,described below. The antiviral lubricous composition can be applied to askin-contacting surface located on at least one of an internal surfaceof the condom or an external surface of the condom, either prior toplacing the condom on or within the penis, finger(s), vagina, anus,mouth, or other body part or object, or afterward. In furtherembodiments, a condom pre-lubricated with any of the antiviral lubricouscompounds of the present invention can be provided in a packaging thatencloses the lubricated condom and seals it from an external environmentoutside of the packaging. In even further embodiments, the packagingcomprises a watertight seal, thereby preventing loss of the antivirallubricous composition before opening the packaging and applying thepre-lubricated condom over the penis or an analogous sexual accessorydevice and engaging in sexual activity. Methods for lubricating condomsand packaging them so they are protected from the outside environmentprior to use during sexual activity are well known in the art.

In some embodiments in which a condom is a substrate, methods forreducing, inhibiting, ameliorating, or preventing the transmission ofHPV between partners engaging in sexual activity further comprise thesteps of: lubricating a skin-contacting surface of a condom; contactingthe skin or epithelial tissue within mouth, vagina, or anus of one ormore of the partners with the lubricated skin-contacting surface of thecondom; and transferring the antiviral lubricous composition from thelubricated skin-contacting surface of the condom to the skin orepithelial tissue

In further embodiments in which the substrate is a condom, methods forreducing, inhibiting, or ameliorating the transmission of HPV betweentwo or more partners engaging in sexual activity further comprise thesteps of: placing a condom over the finger or penis of one partner;lubricating an external surface of the condom with the antivirallubricous composition; contacting the skin or epithelial tissue withinthe mouth, vagina, or anus of one or more additional partners using thelubricated external surface of the condom; and transferring theantiviral lubricous composition from the lubricated external surface ofthe condom to the skin or epithelial tissue.

In other further embodiments in which the substrate is a condom, methodsfor reducing, inhibiting, or ameliorating the transmission of HPVbetween two or more partners engaging in sexual activity furthercomprise the steps of: lubricating the condom; sealing the lubricatedcondom within a packaging; storing the lubricated condom within thepackaging; removing the lubricated condom from the packaging; applyingthe lubricated condom to the finger or penis of one of the sexualpartners; contacting the skin or epithelial tissue within the mouth,vagina, or anus of one or more additional partners using the lubricatedcondom; and transferring the antiviral lubricous composition from thelubricated condom to the skin or epithelial tissue.

In another embodiment, the substrate is an internal applicator. Internalapplicators suitable for use in conjunction with methods of the presentinvention include can any object, device, or accessory that can beconfigured to be inserted into a person's body cavity and is capable oftransferring the antiviral lubricous composition to epithelial tissuewithin the person's body cavity. Non-limiting examples of internalapplicators that can be utilized in accordance with methods of thepresent invention include syringes, pipettes, swabs, cannulas, elongatesticks or rods, and wearable inserts, comprising materials including butnot limited to rubber, latex, plastic, wood, and/or metal. Such examplesare described in U.S. Pat. Nos. 2,546,754, 4,557,720, 4,808,166,6,503,220, 6,537,260, 7,442,179, 7,591,808, 9,290,551, 9,757,549, and9,884,173, the disclosures of which are included by reference in theirentireties. Those skilled in the art would understand that there arecountless other examples of internal applicators, both commerciallyavailable and improvised, to which antiviral lubricous compositions ofthe present invention can be applied and can be inserted into a bodycavity in order to transfer the antiviral lubricous composition toepithelial tissue within the body cavity.

In another embodiment, the internal applicator comprises askin-contacting surface that is configured to contact epithelial tissuewithin a person's body cavity, particularly within the vagina or rectum.In other embodiments, the internal applicator comprises a containerconfigured for housing or containing the antiviral lubricous compositionprior to transferring the antiviral lubricous composition ontoepithelial tissue within a person's body cavity. In either instance, theinternal applicator can be provided in a packaging either with orwithout the antiviral lubricous composition. In further embodiments, theinternal applicator is pre-lubricated with the antiviral lubricouscomposition and sealed within the packaging, protecting the lubricatedinternal applicator from the external environment and preventing loss ofthe antiviral lubricous composition before transfer to epithelial tissuewithin the person's body cavity. Methods for applying lubricants ortherapeutic substances to internal applicators and packaging them arewell known in the art.

Processing of the Antiviral Lubricous Compositions

The antiviral lubricous compositions made by processes of the presentinvention are unique in that they have the ability to inhibit HPV andhave an optimized viscosity, lubricity, and sensation that enhance theirperformance as lubricants during sexual activity, while at the same timeminimizing the osmolality of the composition. In one embodiment of theinvention, the processes to form antiviral lubricous compositions of thepresent invention can comprise the steps of: (a) providing a carrageenanpowder comprising carrageenan, the carrageenan comprising at least about90% by weight λ carrageenan and up to about 10% by weight ι carrageenan;(b) combining, while mixing, the carrageenan powder with an aqueoussolution comprising a polyol to form a turbid carrageenan suspension;and (c) heating the turbid carrageenan suspension up to a temperature ofat least 60° C. and mixing for a time sufficient to transform the turbidcarrageenan suspension into a clarified homogeneous solution, therebyforming the antiviral lubricous composition; wherein (i) the antivirallubricous composition comprises about 0.5% to about 2.3% by weightcarrageenan, and up to about 10% by weight polyol; (ii) the antivirallubricous composition has a viscosity of less than about 5,000 cP; (iii)the antiviral lubricous composition is translucent; and (iv) theantiviral lubricous composition is effective in reducing, inhibiting, orameliorating the transmission of human papillomavirus (HPV).

In another embodiment, processes to form antiviral lubricouscompositions of the present invention can additionally comprise apre-mixing step in which the carrageenan powder and the polyol are firstcombined to form a wet carrageenan mixture comprising carrageenan andpolyol. Without being limited by a particular theory, it is believedthat pre-mixing and dispersing the carrageenan powder within the polyolprior to adding water causes the carrageenan polysaccharides topartially unwind, making additional polarizable contacts available tointeract upon addition of the aqueous solution. Pre-mixing is believedto have several advantages, including but not limited to: mixing atlower speeds and under lower shear conditions; heating at lowertemperatures to homogenize the carrageenan within the aqueous solution;speeding up each mixing step, particularly mixing to homogenize thecarrageenan within the aqueous solution; and preserving the carrageenanpolysaccharides from breaking into smaller segments, which cannegatively affect the viscosity and performance of the composition as apersonal lubricant (see below). In further embodiments, processes toform antiviral lubricous compositions of the present invention cancomprise the steps of: (a) providing a carrageenan powder comprisingcarrageenan, the carrageenan comprising at least about 90% by weightλ-carrageenan and up to about 10% by weight ι-carrageenan; (b) mixingthe carrageenan powder with a polyol to form a wet carrageenan mixture,wherein the weight ratio of the glycol to the carrageenan is about 1:1to about 10:1; (c) combining, while mixing, the wet carrageenan mixturewith an aqueous solution to form a turbid carrageenan suspension,wherein the volume ratio of the aqueous solution to the carrageenan isabout 45:1 to about 8:1; (d) heating the turbid carrageenan suspensionup to a temperature of at least 60° C. and mixing for a time sufficientto transform the turbid carrageenan suspension into a clarifiedhomogeneous solution, thereby forming the antiviral lubricouscomposition; wherein (i) the antiviral lubricous composition comprisesabout 0.5% to about 2.3% by weight carrageenan, and up to about 10% byweight polyol; (ii) the antiviral lubricous composition has a viscosityof less than about 5,000 cP; (iii) the antiviral lubricous compositionis translucent; and (iv) the antiviral lubricous composition iseffective in reducing, inhibiting, or ameliorating the transmission ofhuman papillomavirus (HPV).

In particular, the viscosity of the antiviral lubricous composition isan important factor in its performance as a personal lubricant that canbe used in conjunction with sexual activity. Ideally, personallubricants have a viscosity thick enough to be applied onto the skin orepithelial tissue and remain there until sexual activity is initiated,while also having a rheological profile that the lubricity and moisturefrom the composition is retained throughout the entire duration of thesexual activity. The presence of carrageenan in a composition istypically antithetical to sexual lubricant performance because theviscosity of the composition exponentially increases as a function ofcarrageenan concentration (see Example 3, below).

Similarly, the viscosity of the antiviral lubricous composition issensitive to the balance of several factors in addition to totalcarrageenan concentration, including but not limited to: the identityand relative concentration of the κ-, ι-, and λ-forms of thecarrageenan; the concentration and identity of additional components,particularly polyols; and the weight ratio of the carrageenan to thepolyol, where the polyol is present. Additionally, the viscosity is alsodependent on the processing steps themselves, including but not limitedto: the heating of one or more of the wet carrageenan mixture, thecarrageenan suspension, and/or the antiviral lubricous composition; therate of addition of any of the composition components; the rate andduration of any of the mixing steps; and the type of rotor used formixing. In sum, all the factors above must be tuned to optimize theperformance of the antiviral lubricant compositions during sexualactivity.

In another embodiment, the viscosity of the antiviral lubricouscomposition depends not only on the total carrageenan concentration butalso the relative concentration of the κ-, ι-, and λ-forms ofcarrageenan differentially affect the rate of exponential growth of theviscosity of the antiviral lubricous composition. As an example, thepresence and increasing concentration of κ-carrageenan causes thesteepest increase in the composition's viscosity, whereas the rate ofexponential growth caused by the presence and increasing concentrationof ι-carrageenan is less than that of κ-carrageenan, and the rate ofexponential growth caused by the presence and increasing concentrationof λ-carrageenan is less than both κ-carrageenan and ι-carrageenan.Thus, a composition that is predominantly λ-carrageenan will have alower viscosity than a composition that is predominantly κ-carrageenanand/or ι-carrageenan. As a result and as described above, antivirallubricous compositions of the present invention can comprise greaterthan or equal to about 90% λ-carrageenan and up to about 10% of one orboth of κ-carrageenan or ι-carrageenan. In even further embodiments, theantiviral lubricous compositions comprise about 90% of λ-carrageenan andabout 10% of ι-carrageenan.

Additionally, the physical form in which carrageenan mixtures areobtained also affects how they must be processed. When carrageenans areobtained as raw extracts, they are already in a predominantly liquidstate. However, the shelf life of raw carrageenan extracts is typicallyreduced relative to solid powders, and carrageenan extracts can includecomponents that are unwanted or even harmful. Consequently, obtainingdried carrageenans in powder form for use in the food or pharmaceuticalindustry is common, but comes with the trade-off that the carrageenansmust be re-solubilized in order to be utilized in a liquid composition.

In applications in which carrageenans are ultimately used as thickeningagents, the carrageenan powders can be solubilized simply by high-sheerand high-speed mixing conditions for an extended period of time, oftenalso under aggressive heating conditions. However, carrageenan powderscannot be processed in the same way to produce the antiviral lubricouscompositions of the present invention because such conditions cause theresulting compositions to lose their lubricity over time, particularlyupon undergoing the shear-thinning stress that occurs during sexualactivity. Without being limited by a particular theory, it is believedthat the length of the carrageenan polysaccharides is directlycorrelated with the lubrication and moisture of the resultingcomposition. As the average length of the polysaccharides increase, thelubricity of the composition also increases. On the other hand,solubilizing carrageenan powders under high-shear and high-stressconditions causes the resulting compositions to prematurely dry out.

In another embodiment, the solubilization of carrageenan powders can beassisted by the addition of the powders to a polyol. As described above,polyols are commonly included in personal lubricant compositions becauseof the pleasing properties their presence provides during sexualactivity. The multiple hydroxyl groups in each polyol molecule have anadded benefit because they provide intermolecular contacts with whichindividual sugars within the larger carrageenan polysaccharide caninteract in solution. Without being limited by another theory, it isbelieved that as the amount of the polyol mixed with the carrageenanpowder to form the wet carrageenan mixture increases, the number ofpolar functional groups within each carrageenan polysaccharide thatbecomes available to interact with and solubilize within the aqueoussolvent also increases, causing a concurrent increase in the viscosityof the antiviral lubricous composition.

Previous antiviral lubricous compositions that include a polyol inconjunction with a λ-carrageenan lubricant composition have beensynthesized by simply adding the carrageenan powder to a bulk solventthat included over 37% by weight of 1,2-propanediol (see Example 1,below). At these concentrations, the 1,2-propanediol concentrationcauses an unsafe increase in the osmolality of the composition. However,it was determined that simply reducing the polyol concentration withinthe solvent did not permit the complete homogenization of thecarrageenan powder, even with heating up to 75° C. Instead, a pluralityof “hydro-sealed” clumps containing dry carrageenan powder surrounded bysemi-hydrated carrageenan molecules that were impenetrable to theaddition of water were formed. A similar phenomenon was observed in the'098 patent (described above), even with dry powders that were merelyexposed to water-containing atmospheric conditions.

In some embodiments, processes to form the antiviral lubricouscompositions of the present invention can include a step of first mixingcarrageenan powders with at least one polyol to form a wet carrageenanmixture, prior to the addition of the carrageenans. In furtherembodiments, first solubilizing the carrageenan powder into the polyolfacilitates the complete homogenization of the carrageenanpolysaccharides within the antiviral lubricous composition.

Additionally, the identity of the polyol and the weight ratio of thepolyol to carrageenan also has an effect on the viscosity of theantiviral lubricous composition. As a non-limiting example,1,2-propanediol is approximately 50 times more viscous than water, butglycerol is approximately 23 times more viscous than 1,2-propanediol.Thus, an antiviral lubricous composition can comprise a much greaterconcentration of 1,2-propanediol than a second composition comprisingglycerol, while having the same viscosity. As a result and in anotherembodiment, the weight ratio of the polyol to the carrageenan within thewet carrageenan mixture is at least 1:10, including at least 1:5, 1:1,2:1, 4:1, 6:1, 8:1, 10:1, 20:1, 30:1, or 40:1, up to at least 50:1. Infurther embodiments, the weight ratio of the polyol to the carrageenanis about 1:1 to about 10:1. In even further embodiments, the polyol is1,2-propanediol.

Similarly, the weight ratio of the aqueous solution mixed with the wetcarrageenan mixture to form the carrageenan suspension also affects theviscosity of the antiviral lubricous composition. In some embodiments,as the weight ratio of the aqueous solution relative to the wetcarrageenan mixture increases, the viscosity of the antiviral lubricouscomposition decreases. In further embodiments, the weight ratio of theaqueous solution mixed with the wet carrageenan mixture to form thecarrageenan suspension is about 3:1 to about 60:1. In even furtherembodiments, the weight ratio of the aqueous solution mixed with the wetcarrageenan mixture to form the carrageenan suspension is about 8:1 toabout 45:1.

In another embodiment, heating one or more of the wet carrageenanmixture, the carrageenan suspension, and/or the antiviral lubricouscomposition enables the solubilization and homogenization of thecarrageenans in water. Without being limited by a particular theory, itis believed that heating the carrageenans causes at least a partialunfolding of each carrageenan polysaccharide as well as a disruption ofintermolecular interactions between polysaccharides, both of whichincreases the viscosity of the composition. As heating continues, thecarrageenan polysaccharides begin to solubilize within the aqueoussolution, decreasing the viscosity and forming a homogenous antivirallubricous composition. However, if the composition continues to beheated after all of the carrageenans have been homogenized, theviscosity of the composition can continue to decrease, and thepolysaccharides themselves can dissociate into smaller and smalleroligosaccharides that have lower molecular weights and chain lengths. Infurther embodiments, the carrageenan suspension is heated until anantiviral lubricous composition is formed that has a viscosity of lessthan about 5,000 cP. In even further embodiments, the carrageenansuspension is heated until an antiviral lubricous composition is formedthat has a viscosity of about 1,000 cP to about 4,000 cP.

Compositions comprising carrageenans, such as the carrageenansuspension, that have not been homogenized are typically cloudy, hazy,or turbid, comprising large numbers of carrageenan particles that arevisible by the naked eye. Without being limited by a particular theory,it is believed that the turbidity of the carrageenan suspension resultsfrom aggregate formation between two or more carrageenan polysaccharidesbefore they have been fully unwound and exposed to the aqueous solvent.In another embodiment, the carrageenan suspension is heated until atranslucent antiviral lubricous composition is formed. In furtherembodiments the carrageenan suspension is heated until a transparentantiviral lubricous composition is formed. Within such embodiments, thetranslucent and/or transparent properties of the antiviral lubricouscomposition is maintained even after packaging and/or storage for anextended period of time. In even further embodiments, there aresubstantially zero particulates, aggregates, or agglomerates that arevisible within the antiviral lubricous composition. In still furtherembodiments, the fully homogenized antiviral lubricous composition is asolution.

The turbidity of any of the mixtures, suspensions, or antivirallubricous compositions disclosed herein can be described quantitativelybased on the method of determining the concentration of suspendedparticles in the sample, including but not limited to: FormazinNephelometric Units (FNU), Jackson Turbidity Units (JTU), NephelometricTurbidity Units (NTU), optical density, Helms Units, parts per million(PPM), and others. FNU and NTU are widely used to describe the turbidityof compositions having a uniform distribution of small particles, andare determined by measuring the amount of light that is scattered at 90degrees relative to an incident light beam. In particular, NTU ismeasured using visible light as the incident light beam, typicallybetween about 400 nm and about 680 nm, whereas FNU is measured usinginfrared light as the incident light beam, typically between about 780nm and about 900 nm.

In another embodiment, the turbidity of any of the mixtures,suspensions, or antiviral lubricous compositions described herein arecharacterized as a function of NTU. In even further embodiments, theturbidity of the carrageenan suspension upon the addition of carrageenanto the aqueous solution is at least about 100 NTU, including at leastabout 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, or 3000 NTU,up to at least about 4000 NTU. In other even further embodiments, theturbidity of the homogenized antiviral lubricous composition is lessthan about 25 NTU, including less than about 20, 15, 10, 8, 6, 5, 4, 3,or 2 NTU, down to less than about 1 NTU. In still further embodiments,the turbidity of the homogenized antiviral lubricous composition is lessthan or equal to about 5 NTU.

In other embodiments, antiviral lubricous compositions, particularlyantiviral lubricous compositions that can come in contact with the mouthduring sexual activity, made by processes of the present invention canbe homogenized until it has a turbidity that is approximately equal tothe turbidity of drinking water. Governments, health organizations, andother regulatory bodies have described safety standards to protectpeople and animals from potentially dangerous health conditions fromagents that increase the turbidity of a solution, including but notlimited to: polymers and other macromolecules; insoluble smallmolecules; and bacteria and other microorganisms. The WHO has determinedthat drinking water should not be more than 5 NTU, and should ideally bebelow 1 NTU. In the United States, systems that utilize conventional ordirect filtration methods must decrease the turbidity of drinking waterto less than 1 NTU, and several localities strive to achieve turbiditylevels less than 0.1 NTU.

In another embodiment, the type of mixing apparatus, the rotationalspeed, and the mixing time can be optimized to control the viscosity ofthe resulting antiviral lubricous composition, and to disperse andhomogenize the carrageenan into the aqueous solution. In someembodiments, mixing can be conducted under low-shear conditions for anextended and sufficient time to homogenize the composition, whilepreserving the length of each carrageenan polysaccharide and maintainingtheir lubricity prior to applying the composition to the skin orepithelial tissue, particularly before or in conjunction with sexualactivity. In contrast and in other embodiments, mixing can be conductedunder high-shear conditions for a minimum period of time, but mixingbeyond a minimum time can irreparably disrupt the carrageenanpolysaccharides, decrease the viscosity of the composition, and diminishthe composition's performance as a lubricant during sexual activity.Non-examples of mixers include, but are not limited to, screw mixers,tumble mixers, ribbon mixers, and paddle mixers. In even furtherembodiments, a paddle mixer can be used for each of the mixing steps forforming the antiviral lubricous composition. Similarly, mixing atrelatively low speeds also preserves the structural integrity of eachpolysaccharide. In other even further embodiments, each of the mixingsteps is conducted with a mixing speed of equal or less than about 500RPM. In still further embodiments, mixing of the antiviral lubricouscomposition after homogenizing the carrageenan within the aqueoussolution can occur at speeds less than or equal to about 250 RPM.

In another embodiment, processes for forming the antiviral lubricouscomposition can further comprise several steps, including: (e) coolingthe homogenized antiviral lubricous composition until the temperature ofthe antiviral lubricous composition is less than about 30° C.; (f)mixing one or more pH-adjusting agents into the cooled antivirallubricous composition, at a weight sufficient to adjust the antivirallubricous composition to a pH of about 3.5 to about 7.0; (g) optionallymixing one or more sweeteners into the carrageenan suspension or thecooled antiviral lubricous composition, at up to 0.5% by weight of theantiviral lubricous composition; and (h) optionally mixing one or morepreservatives into the carrageenan suspension or the cooled antivirallubricous composition, at up to 1% by weight of the antiviral lubricouscomposition. In further embodiments, each of the additional components,such as the pH-adjusting agents, sweeteners, and preservatives describedabove, as well as salts and/or aromatic agents, can be included withinthe antiviral lubricant composition to supplement its anti-HPV activityand/or enhance its performance during sexual activity. Compositionproperties as a result of adding pH-adjusting agents, sweeteners, andpreservatives are described above.

In another embodiment, the processes described above can be utilized tohomogenize carrageenan mixtures having different λ-, κ, andι-carrageenan ratios into an aqueous solvent at any desired viscosity.In some embodiments, λ-carrageenan comprises at least about 50% byweight of the carrageenan powder, including at least about 60 or 70% byweight, up to about 80% by weight of the carrageenan powder. In otherembodiments, λ-carrageenan comprises less than about 85, 80, or 70% byweight, down to less than about 60% by weight of the carrageenan powder.Within such embodiments, the amount of κ- and ι-carrageenans canincrease such that when present, κ-carrageenan and ι-carrageenantogether comprise up to about 50% by weight of the carrageenan powder,including up to 40%, 30%, or up to 20% by weight of the carrageenanpowder.

While particular embodiments of the invention have been described, theinvention can be further modified within the spirit and scope of thisdisclosure. Those skilled in the art will recognize or be able toascertain using no more than routine experimentation, numerousequivalents to the specific procedures, embodiments, claims, andexamples described herein. As such, such equivalents are considered tobe within the scope of the invention, and this application is thereforeintended to cover any variations, uses or adaptations of the inventionusing its general principles. Further, the invention is intended tocover such departures from the present disclosure as come within knownor customary practice in the art to which this invention pertains andwhich fall within the appended claims.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

The contents of all references, patents, and patent applicationsmentioned in this specification are hereby incorporated by reference andshall not be construed as an admission that such reference is availableas prior art to the present invention. All of the incorporatedpublications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains and are incorporated to the same extent as if eachindividual publication or patent application was specifically indicatedand individually indicated by reference.

Because the instant application is a continuation application, to theextent any amendments, characterizations, or other assertions previouslymade (in any related patent applications or patents, including anyparent, sibling, or child) with respect to any art, prior or otherwise,could be construed as a disclaimer of any subject matter supported bythe present disclosure of this application, Applicant hereby rescindsand retracts such disclaimer. Applicant also respectfully submits thatany prior art previously considered in any related patent applicationsor patents, including any parent, sibling, or child, may need to bere-visited.

The invention is further illustrated by the following working andprophetic examples, neither of which should be construed as limiting theinvention. Additionally, to the extent that section headings are used,they should not be construed as necessarily limiting. Any use of thepast tense to describe an example otherwise indicated as constructive orprophetic is not intended to reflect that the constructive or propheticexample has actually been carried out.

EXAMPLES

The following working and prophetic examples illustrate the embodimentsof the invention that are presently best known. However, it is to beunderstood that the following are only exemplary or illustrative of theapplication of the principles of the present invention. Numerousmodifications and alternative compositions, methods, and systems may bedevised by those skilled in the art without departing from the spiritand scope of the present invention. Thus, while the present inventionhas been described above with particularity, the following examplesprovide further detail in connection with what are presently deemed tobe the most practical and preferred embodiments of the invention.

WORKING EXAMPLES Example 1: Preparation of High-Osmolality PersonalLubricant Composition

The following antiviral lubricous composition was prepared in accordancewith the procedure used to make commercial preparations of theλ-carrageenan-based personal lubricant, Divine 9®.

Ingredients

55.70% (w/w) deionized water 37.40% (w/w) 1,2-propanediol 5.00% (w/w) of2.5% (w/v) sodium saccharin solution in deionized water 1.40% (w/w)Viscarin ® PC 209 carrageenan powder 0.04% (w/w) citric acid 0.01% (w/w)sodium hydroxide 0.95% (w/w) GeoGard ECT preservative (Lonza ConsumerCare) 0.03% (w/w) GeoGard 111 - Sodium Dehydroacetate preservative(Lonza Consumer Care)

All ingredients were combined except the Viscarin® PC 209 carrageenanpowder and mixed together thoroughly. With constant mixing, thecomposition was then gradually heated up to 75° C. When the compositionreached 50° C., Viscarin® PC 209 carrageenan powder was graduallycombined until all of the carrageenan powder was added. The compositioncontinued to be mixed at 75° C. until all of the Viscarin® PC 209carrageenan powder was dissolved, about two hours. Upon dissolution ofthe carrageenan powder, mixing was ceased and the composition was cooledrapidly. Once the temperature of the composition reached 30° C., citricacid was added to bring the pH to about 6.5, +/−0.25.

Example 2: Preparation of a Low-Osmolality Antiviral LubricousComposition

The following antiviral lubricous composition was prepared in accordancewith embodiments of the present invention and the procedure below:

Ingredients

88.49% (w/w) deionized water 4.40% (w/w) 1,2-propanediol 5% (w/w) of2.5% (w/v) Sodium saccharin solution in deionized water 1.60% (w/w)Viscarin ® PC 209 carrageenan powder 0.05% (w/w) citric acid 0.32% (w/w)2-phenoxyethanol 0.11% (w/w) chlorphenesin 0.03% (w/w) GeoGard 111 -Sodium Dehydroacetate preservative (Lonza Consumer Care)

The Viscarin® PC 209 carrageenan powder and 1,2-propanediol were mixedfor approximately 10 minutes to form a wet carrageenan mixture, using aMixer Direct R-AD665 industrial gallon paddle mixer with two foldingimpeller blades, operating at 500 RPM. After 10 minutes, no aggregateparticles of powder were observed within the wet carrageenan mixture.With continued mixing, approximately 90% of the volume of the water andall of the saccharin was added to the wet carrageenan mixture over anadditional 5 minutes, forming a turbid carrageenan suspension. Thecarrageenan suspension was heated to 70° C. and allowed to mix under thesame mixing conditions until the carrageenan powder was completelyhomogenized within the water. Homogenization was achieved upon atransition from a turbid suspension into a clarified solution, afterabout 90 minutes. Mixing continued for 10 more minutes afterhomogenization took place. The mixer was paused and the composition wascooled to less than 30° C. Once cooled, the preservatives, citric acid,and remaining water were added to the composition, with mixing at 250RPM for 20 minutes. The resulting antiviral lubricous composition wastranslucent and has a pH of about 6.5, +/−0.25.

Example 3: Exponential Effect of Carrageenan Concentration onComposition Viscosity

In order to evaluate the effect of the carrageenan on the viscosity ofantiviral lubricous compositions, several compositions were formulatedat varying concentrations of the carrageenan. A first sample, Sample V1,was prepared according the same ingredient specifications and procedureas the composition of Example 1. Additional antiviral lubricouscompositions (Samples V2-V5) with different concentrations ofcarrageenan were prepared, using the procedure of Example 2. The volumeof water added was adjusted as necessary. The final volume for eachsample composition of 200 mL. The concentration of carrageenan andviscosity of each sample are provided in Table 2, below.

TABLE 2 Measured Viscosities of Antiviral Lubricous Compositions SampleNumber Carrageenan powder (w/v) Measured Viscosity (cP) V1 1.40 1975 V21.73 2900 V3 2.10 4000 V4 2.15 4400 V5 2.20 4750

Each of the viscosity measurements were taken using a Brookfield LVFDial Reading Viscometer, using a #2 spindle at 12 revolutions perminute, according to instructions provided with the instrument. Therelationship between the viscosity of the antiviral lubricouscomposition as a function of the carrageenan concentration isillustrated in FIG. 1. Fitting the data to an exponential model usingMicrosoft Excel yields a trendline with an R² value of 0.994, indicatinga strong correlation between the data and the model.

Example 4: Linear Effect of 1,2-Propanediol on Composition Osmolality

In order to evaluate the effect of 1,2-propanediol on the osmolality ofantiviral lubricous compositions, several compositions were formulatedat varying concentrations of the 1,2-propanediol. A first sample, SampleO1, was prepared according the same ingredient specifications andprocedure as the composition of Example 1. Additional antivirallubricous compositions (Samples O2-O5) with different concentrations of1,2-propanediol were prepared, using the procedure of Example 2. Thevolume of water added was adjusted as necessary. The final volume foreach sample composition of 50 mL. The concentration of 1,2-propanedioland osmolality of each sample are provided in Table 3, below.

TABLE 3 Measured Osmolality of Antiviral Lubricous Compositions SampleNumber 1,2-propanediol (w/v) Osmolality (mOsmol/kg) O1 37.4 5300 O2 8.81622 O3 6.6 1181 O4 4.4 800 O5 4.0 730

Each of the osmolality measurements were performed with an osmometercapable of measuring freezing point depression, in accordance withUnited States Pharmacopeial Convention standard protocols (see USP<785>, Osmolality and Osmolarity, 2017). The relationship between theosmolality of the antiviral lubricous composition as a function of the1,2-propanediol concentration is illustrated in FIG. 2. Fitting the datato a linear model using Microsoft Excel yields a trendline with an R²value of 0.9974, indicating a strong correlation between the data andthe model

PROPHETIC EXAMPLES Example 5: Characterization of the DisaccharideContent of Antiviral Lubricous Compositions

Each of the primary forms of carrageenan comprises a different repeatingdisaccharide structure—ι-carrageenan comprises alternating disaccharidesof D-galactaose-4-sulfate and 2-sulfo-3,6-anhydro-D-galactose;κ-carrageenan comprises alternating disaccharides ofD-galactose-4-sulfate and 3,6-anyhdro-D-galactose; and λ-carrageenancomprises alternating disaccharides of D-galactose-2-sulfate (1-3linked) and D-galactose-2,6-disulfate (1,4 linked). As a result,λ-carrageenan typically contains more sulfate groups per polymer andsubstantially fewer anhydrogalactose residues, which are commonly foundin ι-carrageenan and κ-carrageenan. Consequently, the relative ratio ofλ- to ι- to κ-carrageenan in an antiviral lubricous composition can bedetermined by several analytical techniques, including but not limitedto infrared spectroscopy (IR), nuclear magnetic resonance (NMR)spectroscopy (see de Araujo, C. A., et al., (2013) Carbohydrate Polymers91:483-491, and liquid chromatography coupled to mass spectroscopy(LC-MS) (see Diez, F., et al., (2017) “Development of an AnalyticalMethod to Determine the amount of ê Carrageenan in HPMC Capsules byLCMS,” American Association of Pharmaceutical Scientists PosterSubmission, obtained from the internet athttp://abstracts.aaps.org/Verify/AAPS2017/PosterSubmissions/M8109.pdf onMay 3, 2018).

In particular, IR spectrum of antiviral lubricous composition can beutilized to determine both a profile of the composition that can becompared against other λ-carrageenan-containing compositions, as well asa relative molar ratio of the λ-, ι- and κ-carrageenan forms within thecomposition (see Volery, P., et al., (2004) J. Agric. Food Chem. 52(25):7457-7463). Within the fingerprint region of a typical IR spectrum(between about 800 cm⁻¹ and about 1250 cm⁻¹), carrageenan has severalstrong, broad absorption bands for residues or functional groupscommonly found within each polymer, as well as a strong absorptionmaximum between about 1065 cm⁻¹ and about 1020 cm⁻¹, particularly about1050 cm⁻¹. The intensity of the absorbance of a particular bandcorresponding to a residue or functional group, relative to theintensity of the major absorption band at 1050 cm⁻¹, can be used todetermine the relative abundance of a particular form of carrageenanwith the IR sample. Characteristic absorption bands and theirintensities relative to the major absorption band at 1050 cm⁻¹ areillustrated below in Table 4.

TABLE 4 Common IR absorption bands in carrageenan Wave Absorbancerelative Number to 1050 cm⁻¹ (cm⁻¹) Molecular Assignment κ ι λ 1220-1260Ester sulfate 0.2-1.2 1.2-1.6 1.4-2.0 928-933 3,6-anydrogalactose0.2-0.6 0.2-0.4  0-0.2 840-850 Galactose-4-sulfate 0.1-0.5 0.2-0.4 —825-830 Galactose-2-sulfate — — 0.2-0.4 810-820 Galactose-6-sulfate — —0.1-0.3 800-805 3,6-anhydrogalactose-2-sulfate  0-0.2 0.2-0.4 —

A study is conducted in accordance with principles of the presentinvention to characterize the carrageenan within a sample of theantiviral lubricous composition. A sample of the antiviral lubricouscomposition is subjected to IR spectroscopic analysis according to theprocedure described in the Food and Agricultural Organization of theUnited Nations/World Health Organization joint compendium of foodadditive specifications (see “Carrageenan, Compendium of Food AdditiveSpecifications FAO JEFCA Monographs 16; FAO/WHO Publications; Rome,Italy; pp. 7-12). It is expected that antiviral lubricous compositionsof the present invention possess a unique and characteristic IR spectrumthat can be compared against other compositions that containλ-carrageenan. It is also expected that the IR spectrum for theantiviral lubricous composition possesses peaks between 810 cm⁻¹ and 820cm⁻¹ as well as 825 cm⁻¹ and 830 cm⁻¹, indicating the presence ofλ-carrageenan within the antiviral lubricous composition. It is furtherexpected that the molar ratio of λ-carrageenan in the antivirallubricous composition is greater relative to the molar ratio ofκ-carrageenan and ι-carrageenan.

I claim:
 1. A method for forming an antiviral lubricous composition,comprising the steps of: (a) providing a carrageenan powder comprisingcarrageenan, the carrageenan comprising about 90% by weightlambda-carrageenan and about 10% by weight kappa-carrageenan; (b) mixingthe carrageenan powder with a solution comprising propylene glycol,forming an aqueous carrageenan suspension; (c) heating the aqueouscarrageenan suspension up to a temperature of at least about 70° C. andup to about 75° C.; (d) mixing the heated aqueous carrageenan suspensionfor a time sufficient to form an aqueous homogenous solution having aturbidity that is less than or equal to about 25 Nephelometric TurbidityUnits (NTU); (e) cooling the aqueous homogeneous solution to atemperature of less than about 30° C.; and (f) mixing in one or morepH-adjusting agents, in an amount sufficient to adjust the antivirallubricous composition to a pH of about 3.5 to about 7.0.
 2. The methodaccording to claim 1, wherein the viscosity of the antiviral lubricouscomposition is about 500 cP to about 10,000 cP.
 3. The method accordingto claim 2, wherein the carrageenan comprises, by weight, about 0.1% toabout 3% of the antiviral lubricous composition.
 4. The method accordingto claim 1, wherein the osmolality of the antiviral lubricouscomposition is about 200 mOsmol/kg to about 1400 mOsmol/kg.
 5. Themethod according to claim 4, wherein the propylene glycol comprises, byweight, about 0.1% to about 8% of the antiviral lubricous composition.6. The method according to claim 1, the method further comprising thestep of adding with mixing up to about 0.5% by weight one or moresweeteners.
 7. The method according to claim 6, wherein the one or moresweeteners are added and mixed into the aqueous carrageenan suspension.8. The method according to claim 1, the method further comprising thestep of adding with mixing up to about 1% by weight one or morepreservatives.
 9. The method according to claim 8, wherein the one ormore preservatives are added and mixed into the cooled aqueoushomogenous solution.
 10. The method according to claim 1, wherein theamount sufficient of the one or more pH-adjusting agents adjusts theantiviral lubricous composition to a pH of about 3.5 to about 5.5. 11.The method according to claim 1, wherein the amount sufficient of theone or more pH-adjusting agents adjusts the antiviral lubricouscomposition to a pH of about 5.5 to about 7.0.
 12. The method accordingto claim 11, wherein the one or more pH-adjusting agents are mixed intothe cooled aqueous homogeneous solution.
 13. The method according toclaim 1, wherein: the carrageenan comprises, by weight, about 1.5% toabout 1.7% of the antiviral lubricous composition; the propylene glycolcomprises, by weight, about 4.0% to about 4.5% of the antivirallubricous composition; the viscosity of the antiviral lubricouscomposition is about 2,000 cP to about 3,000 cP; and the osmolality ofthe antiviral lubricous composition is about 650 mOsmol/kg to about 850mOsmol/kg.
 14. The method according to claim 13, wherein the amountsufficient of the one or more pH-adjusting agents adjusts the antivirallubricous composition to a pH of about 5.5 to about 7.0.
 15. The methodaccording to claim 14, wherein the method further comprises the steps ofadding with mixing up to about 0.5% by weight one or more sweeteners;and adding with mixing up to about 1% by weight one or morepreservatives.
 16. The method according to claim 15, wherein the one ormore sweeteners are added and mixed into the aqueous carrageenansuspension, and the one or more pH-adjusting agents and the one or morepreservatives are added and mixed into the cooled aqueous homogenoussolution.
 17. The method according to claim 16, wherein the step (b)comprises the sub-steps of: (A) mixing the carrageenan powder with anamount of propylene glycol for a time sufficient to form a wetcarrageenan mixture, wherein the weight ratio of the amount of propyleneglycol to the carrageenan powder is about 1:1 to about 10:1; and (B)combining, while mixing, the wet carrageenan mixture with an aqueoussolution for a time sufficient to form the aqueous carrageenansuspension, wherein the volume ratio of the aqueous solution to the wetcarrageenan mixture is about 45:1 to about 8:1.
 18. The method accordingto claim 17, wherein the total mixing time for forming the wetcarrageenan mixture, forming the aqueous carrageenan suspension, formingthe aqueous homogenous solution, and forming the antiviral lubricouscomposition is about three hours or less.
 19. The method according toclaim 1, wherein the step (b) comprises the sub-steps of: (A) mixing thecarrageenan powder with an amount of propylene glycol for a timesufficient to form a wet carrageenan mixture, wherein the weight ratioof the amount of propylene glycol to the carrageenan powder is about 1:1to about 10:1; and (B) combining, while mixing, the wet carrageenanmixture with an aqueous solution for a time sufficient to form theaqueous carrageenan suspension, wherein the volume ratio of the aqueoussolution to the wet carrageenan mixture is about 45:1 to about 8:1. 20.The method according to claim 1, wherein each of the mixing steps areperformed using a paddle mixer.